Immunomodulation and immunotherapy: drugs, cytokines, cytokine receptors, and antibodies

13 Pages·0.197 MB·English

by  Nelson RP Jr, Ballow M.

26. Immunomodulation and
immunotherapy: Drugs, cytokines,
cytokine receptors, and antibodies
Robert P.Nelson,Jr,MD,aand Mark Ballow,MDbIndianapolis,Ind,and Buffalo,NY
The preceding chapters in this primer have provided an
Abbreviations used
overview of the immune response that serves as a background
AITP: Autoimmune thrombocytopenia purpura
for understanding potential sites for immune modulation and
ANCA: Anti-neutrophil cytoplasmic antibodies
immunotherapy. A number of soluble growth and activation
AP-1: Activating protein-1
factors are released from various cell populations involved in
CSA: Cyclosporine A
the immune response. They play vital roles in the initiation,
CRS: Cytokine release syndrome
propagation,and regulation of immunologic responses. Phar-
COX-2: Cyclooxygenase
macologic immunomodulators include suppressive and stimu-
FDA: Food and Drug Administration
latory agents. Immunosuppressive therapies include
GCS: Glucocorticosteroids
antimetabolites,cytotoxic drugs,radiation,adrenocortical glu-
GR: Glucocorticosteroid receptor
cocorticosteroids,immunophilins,and therapeutic antibodies.
GRE: Glucocorticoid response elements
The field of clinical immunostimulation is emerging as an
GVHD: Graft-versus-host-disease
important therapeutic modality for a number of immunodefi-
HCT: Hematopoietic cell transplantation
ciency diseases,chronic viral infections,and cancer. These
ICAM: Intercellular cell adhesion molecule
compounds will be discussed in terms of general principles,
IMDP: Inosine monophosphate dehydrogenase
molecular targets,major indications,and adverse effects. (J
INF: Interferon
Allergy Clin Immunol 2003;111:S720-32.)
ITIM: Immunoregulatory tyrosine-based inhibition
Key words:Immunomodulation,immunosuppressive,cytokines, motif
monoclonal antibodies,biological response modifiers,autoimmu- IVIG: Intravenous immunoglobulin
nity,immunodeficiency,transplantation,glucocorticosteroids, MMF: Mycophenolate mofetil
immunophilins mTOR: Target of rapamycin
NF-κB: Nuclear factor kappa B
An impressive group of therapies that alter immunolog- NF-AT: Nuclear factor of activated T-cells
ic function for the treatment of human disease has been RCC: Renal cell carcinoma
developed. Modalities include irradiation, cytotoxic RSV: Respiratory syncytial virus
chemotherapeutic agents,and glucocorticosteroids (GCS) RSV-IGIV: Respiratory syncytial virus immune globulin
that have been available for many years. They induce intravenous
TEN: Toxic epidermal necrolysis
broad and potent immunosuppressive effects, as well as
TBI: Total body irradiation
frequent,sometimes fatal side effects. Advances in clinical
TNF: Tumor necrosis factor
immunomodulation include dosing modifications of clas-
VZIG: Varicella-zoster immune globulin
sic preparations and implementation of new medications.
VZV: Varicella-zoster virus
Basic immunobiologists have elucidated mechanisms
of immunologic specificity, recognition, activation, reg-
ulation,and tolerance induction that depend on the inter- Immunomodulation also includes therapies that boost
actions of many cell types and their products. These dis- an individual’s defenses by providing either physiologic
coveries have led to the development of therapies that or supraphysiologic dosages of exogenous cytokines to
target components whose altered function results in more treat chronic viral infections and malignancies. Another
focused effects,which may permit selective modulation group of agents stimulate hematopoietic recovery in
of immunologic balance without severe side effects (Fig patients suffering from cytopenias resulting from disease
1). Currently available agents include new classes of or therapy-related bone marrow suppression. Monoclo-
nonspecific immunosuppressive therapies and those nal antibodies and hybrid molecules are important addi-
aimed at specific cells,cytokines,or cytokine receptors. tions; the latter combine the specificity of the immune
therapy with a cytoxic chemical or radiation effect.
Recently approved medications are rapidly becoming
standard primary or adjunctive treatments for patients
From the aIndiana University School of Medicine,Indianapolis,Ind and
bChildren’s Hospital of Buffalo,Buffalo,NY. who are managed by a range of clinicians and all trans-
Reprint requests:R. P. Nelson,Jr,MD,Division of Hematology/Oncology, plant surgeons. This chapter will discuss those therapies
Hematological Malignancy Program/Immunology,535 Barnhill Dr,Ste available for human use at the time of this publication.
473,Indianapolis,IN 46202. The future is bright for clinical immunotherapy, as the
©2003 Mosby Inc. All rights reserved.
basic understanding of human immunophysiology reach-
0091-6749/2003 $30.00 + 0
doi:10.1067/mai.2003.146 es a new scope and dimension.
S720
J ALLERGY CLIN IMMUNOL Nelson and Ballow S721
VOLUME 111, NUMBER 2
FIG 1.Sites of immunomodulation. Steps of both antibody and cell-mediated immune responses to anti-
gens (such as may be involved in autoimmune disease) are numbered in the figure. Examples of different
immunomodulators that can suppress these steps are indicated in letters. For example, Rh (D)immune
globulin (A)prevents the sensitization of the immune system by attaching to foreign red blood cells at the
initial step (Step 1) of antigen-presenting cells. Corticosteroids (B)decrease the reactivity of CD4+cells with
antigen-presenting cells at Step 2. Anti-T-cell antibodies (C)inactivate CD4+T-cells (Step 3). Immunophilins
act within the cells (activated CD4+and CD8+T-cells) to reduce their activation state (Step 3). Antimetabo-
lites and other drugs interfere with the effector function of cytotoxic CD8+T cells and activated B cells that
cause autoimmune disease, for example (Step 4).
IRRADIATION AND DRUGS Azathioprine
Irradiation and chemotherapeutic cytotoxic pharma- Azathioprine is hepatically metabolized to the purine
ceuticals possess potent immunosuppressive activities analogue 6-mercaptopurine after oral administration.
that make them candidates for the treatment of diseases This metabolite incorporates into DNA,which results in
characterized by disordered immunologic function. Irra- death of rapidly dividing cells of the bone marrow and
diation (total body or localized) and cytotoxic or intestine. Six-mercaptopurine prevents or minimizes the
antimetabolite drugs,such as azathioprine,methotrexate, immune-mediated rejection of transplanted organs and
and cyclophosphamide, are the predominant modalities modulates autoimmune diseases, including rheumatoid
in common use at this time for a variety of immunomod- arthritis, Crohn’s disease, ulcerative colitis, and chronic
ulating purposes. Mycophenolate mofetil is a recent graft-versus-host disease (GVHD) after HCT.3,4 Thera-
addition to this group of drugs. peutic immunosuppression occurs at doses of 1.5 mg/kg,
which minimally suppresses leukocyte counts in most
Irradiation
people. Long-term therapy is associated with an
High-dose, total body irradiation (TBI) has profound increased risk of squamous carcinomas of the skin,lym-
immunosuppressive effects that are used for the condi- phoma,and bacterial and opportunistic infections.
tioning of certain patients before hematopoietic cell
Methotrexate
transplantation (HCT). After TBI, 80% of lymphocytes
undergo prompt intermitotic death. Among these are B Methotrexate inhibits dihydrofolate reductase, which
lymphocytes and the precursors to all T-cell subpopula- results in accumulation of inactive oxidized folates and
tions; in addition, the homing activity of cells is affect- cessation of nucleotide synthesis. This activity primarily
ed.1TBI prevents primary immune responses to neoanti- kills cells that are in S-phase (DNA synthesis); nonpro-
gens more effectively than modifying responses to recall liferating cells are resistant. Methotrexate also inhibits
antigens. Alternative approaches include total lymphoid macrophage activation, as demonstrated in an animal
irradiation that is effective for the treatment of Hodgkin’s model of adjuvant arthritis.5 Methotrexate is given to
disease, solid organ graft rejection, and severe rheuma- humans to prevent GVHD after HCT and for the treat-
toid arthritis,and as a component of conditioning prior to ment of rheumatoid arthritis,systemic lupus erythemato-
HCT. Local irradiation, including regional lymph node sus (SLE),and psoriasis.6Weekly oral methotrexate has
irradiation, produces lymphopenia and decreased been suggested to have a steroid-sparing effect in severe
delayed hypersensitivity responses,but does not increase asthmatics; however, the effectiveness of this is contro-
susceptibility to infection.2 versial.7,8Methotrexate has provided short-term efficacy
S722 Nelson and Ballow J ALLERGY CLIN IMMUNOL
FEBRUARY 2003
for the treatment of juvenile rheumatoid arthritis.9 Risk where the activated GR complex binds to DNA sequences
factors for enhanced hematologic toxicity include renal known as glucocorticoid response elements (GRE). This
insufficiency,concomitant nonsteroidal anti-inflammato- process impacts target gene transcription.16 Glucose
ry and trimethoprim-sulfamethoxazole administration, metabolism is mediated by enhancement or inhibition of
intravascular volume depletion, or folate deficiency. gene transcription. Anti-inflammatory effects of GCS result
Long-term use is associated with hepatic fibrosis that from the inhibition of transcription by direct GRE-DNA
leads to cirrhosis in some patients,a complication that is binding or by the production of proteins that have inhibito-
not uniformly predicted by hepatocellular enzyme eleva- ry effects on target gene transcription.17Pro-inflammatory
tion. Periodic liver biopsy should be considered for long- cytokines IL-1, IL-2, IL-6, IL-8, interferon (IFN)-γ and
term recipients of the drug.10Methotrexate is teratogenic tumor necrosis factor (TNF)-αare inhibited. GCS enhance
and should be avoided, if possible, in pregnant women; the production of lipocortin,which inhibits phospholipase
but it does not appear to be carcinogenic. A ,interrupting arachidonic acid metabolism at the mem-
2
brane level.17This results in broad and potent reductions in
Cyclophosphamide
leukotriene synthesis, which partially mediates the anti-
Cyclophosphamide is an alkylating agent that forms asthmatic activity. GCS inhibit cyclooxygenase gene
covalent bonds with DNA,thereby leading to DNA frag- (COX-2) transcription,a rate-limiting enzyme for the pro-
mentation,mutations,and cell death. It suppresses cellu- duction of prostaglandins, whereas IL-1 opposes this
lar immunity and inhibits antibody and autoantibody pro- action. Collagenase,an enzyme that degrades tissue at sites
duction. The primary use for cyclophosphamide is as of inflammation, is inhibited at the transcription level by
conditioning therapy before HCT and for the treatment of binding of the GR complex to the proto-oncogene product,
SLE and vasculitis. A single daily dose is typically used c-JUN, which is a component of the activating protein-1
for the treatment of Wegener’s granulomatosis, whereas (AP-1) transcription factor complex. AP-1 activity is then
monthly “pulse” therapy, usually in combination with downregulated,which prevents collagenase gene transcrip-
maintenance oral prednisone, is the approach for the tion.18Finally,GCS inhibit nitric oxide synthetase,which
treatment of SLE with nephritis.11,12 Adverse effects decreases production of nitric oxide, a potent vasodilator
include leukopenia, sterility, hemorrhagic cystitis, and and mediator of inflammation.19The biomedical effects of
malignancy, including leukemias and transitional cell this broad inhibition of proinflammatory mediators are the
carcinoma. A thorough review of these potential effects reduction of tissue destruction,vasodilatation,vascular per-
should be undertaken with the family and documented in meability,and acute phase reactivity. GCS alter the circu-
the medical record before treatment. Consideration of lating number and function of neutrophils, eosinophils,
storage of sperm or ova should be raised with young macrophages, and lymphocytes.20 Neutrophils are
adults before therapy. increased in the circulation, but are reduced at sites of
inflammation by glucocorticoid-mediated downregulation
Mycophenolate mofetil
of endothelial adhesion molecules,intercellular cell adhe-
Mycophenolate mofetil (MMF) is an ester of sion molecule (ICAM),and endothelial leukocyte adhesion
mycophenolic acid that inhibits the enzyme inosine molecule-1. Activation of neutrophils is reduced,at least in
monophosphate dehydrogenase (IMDP), thus inhibiting part, by glucocorticoid-mediated IL-8 inhibition.
the de novo pathway of guanosine nucleotide synthesis, Eosinophil adherence and degranulation are inhibited.
without incorporating into DNA. T- and B lymphocytes Monocyte-mediated effects are inhibited by the interfer-
are critically dependent on de novo purine synthesis for ence with recruitment, Fc-receptor function, antigen pro-
DNA replication,whereas other cell types rely on nucle- cessing,and major histocompatibility complex class II and
oside salvage pathways. Therefore, MMF exposure IL-1 production. Lymphocyte traffic is rerouted from recir-
results in potent cytostatic effects on T- and B lympho- culating to nonrecirculating pools in the lymph nodes and
cytes. MMF inhibits T-cell proliferation after mitogen bone marrow. Immature lymphocytes and thymocytes are
and allogeneic stimulation, inhibits antibody production susceptible to glucocorticoid-induced apoptosis in experi-
by B lymphocytes, and prevents glycosylation of adhe- mental models. T-cell proliferation to soluble and cellular
sion proteins.13 The latter effect inhibits recruitment of antigens and production of IL-2 is inhibited. B cells are
lymphocytes to inflammatory foci. It is used to prevent redistributed,but immunoglobulin production is not direct-
organ rejection in renal, cardiac, and hepatic allotrans- ly inhibited, although serum IgG levels may be lower in
plant recipients,and is usually given in conjunction with subjects treated with GCS resulting from cytokine-mediat-
GCS and cyclosporine.14,15 It also is being investigated ed pathways or increased immunoglobulin metabolism.
for the treatment of several autoimmune diseases. Thus, it is important to recognize that steroid-dependent
asthmatics may have low total IgG levels because of
Glucocorticosteroids
increased metabolism, rather than decreased production.
GCS are extremely potent,anti-inflammatory/immuno- This makes immunoglobulin replacement therapy an
suppressive hormones; their actions are mediated by a vari- uncommon necessity for the treatment of severe asthma.
ety of mechanisms that alter cell numbers and function. The diverse anti-inflammatory and immunosuppres-
Steroid molecules interact with an intracytoplasmic gluco- sive activities of GCS translate into potent clinical effects
corticosteroid receptor (GR) that migrates into the nucleus, for the treatment of allergic, dermatologic, and autoim-
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VOLUME 111, NUMBER 2
TABLE I.Relative pharmacologic potencies, equivalent dosage, and biologic and plasma half-life (t1/2) of GCS prepara-
tions
Anti-inflammatory Equivalent pharmacologic Mineralocorticoid Plasma Biologic HPA axis
potency* dose (mg) potency† t 1⁄2(hr) t 1⁄2(hr) suppression (mg)‡
Hydrocortisone 1 20 2 1.5 8-12 20-30
Cortisone 0.8 25 2 1.5 8-12 20-35
Prednisone 2.7 5 1 2.7 12-36 7.5
Prednisolone 4 5 1 2.75 12-26 7.5
Methylprednisolone 5 4 0 3 12-26 7.5
Triamcinolone 5 4 0 4.2 24-48 5-7.5
Dexamethasone 30 0.75 0 5 36-54 1-1.5
*Relative to hydrocortisone,which is assigned a value of 1.
†Range,0-4.
‡Daily dose that usually leads to HPA suppression.
mune diseases. GCS are used to prevent GVHD and graft morning administration. A relatively recent modification is
rejection in HCT and solid organ allograft recipients, the administration of a large bolus or “pulse”dose (ie,sol-
respectively. GCS are paradoxically used in conjunction umedrol, 15-30 mg/kg) daily for 1 to 3 days, at monthly
with antimicrobial therapy for the treatment of Pneumo- intervals, to achieve potent anti-inflammatory activity
cystis cariniipneumonia,in which case their anti-inflam- while limiting daily chronic exposure. The efficacy of such
matory activity improves oxygenation and decreases treatment has been evaluated in controlled studies with
clinical progression to ventilator dependence, whereas patients with rheumatoid arthritis,SLE nephritis,and inter-
the antimicrobial drug eliminates the organism. stitial lung disease. A general guide for clinicians treating
Multiple systemic GCS are available for clinical use, allergic, inflammatory, and autoimmune conditions is to
and a large variety of agents may be topically applied to use sufficient quantities to control the disease,then reduce
the skin, conjunctiva, nasal mucosa, rectal mucosa, or to the lowest dose necessary to maintain disease remission
delivered to pulmonary tissue by inhalation. The plasma while limiting side effects. Adverse effects are minimized
half-life of GCS is the time required for disappearance by alternate-day oral administration,pulse therapy,the use
into tissues of half the circulating plasma concentration. of topical preparations,and the incorporation of adjunctive
The biological half-life is a measure of the duration of nonsteroidal anti-inflammatory/immunosuppressive med-
anti-inflammatory activity,which approximates the dura- ications. These strategies may permit the avoidance of the
tion of hypothalamic-pituitary suppression. Tissue toxicities that universally occur in patients given supra-
effects are estimated, therefore, by metapyrone testing physiologic dosages of daily exogenous GCS.21
and may persist long after the GCS have disappeared The predominant serious side effects in adults are the
from the circulation. The glucocorticoid potency of cor- development of glucose intolerance, weight gain, osteo-
tisol is dependent on its 11-beta hydroxyl group; 11-keto porosis,hypertension,gastritis,cataracts,and,occasional-
compounds (cortisone and prednisone) must be convert- ly, aseptic necrosis of the large joints, psychogenic
ed to the corresponding 11-beta hydroxyl compound to effects,and susceptibility to viral,fungal,and mycobacte-
be active. Prednisolone or methylprednisolone, 11-beta rial infections. It is important to recognize that long-term
hydroxyl compounds,may be preferred for patients with hypothalamic pituitary axis suppression occurs. Long-
impaired liver function or congestive heart failure. term GCS recipients should be treated with higher
GCS can be divided into three groups,based on plasma dosages (ie,two to three times maintenance) before major
and biologic half-lives:short-acting,intermediate-acting, surgical procedures. Fatal Addisonian crises after general
and long-acting drugs. Hydrocortisone is a short-acting surgical procedures during steroid withdrawal occur,
form of GCS that is assigned an anti-inflammatory and albeit rarely. Growth failure complicates GCS use in chil-
endocrine potency of 1 and a sodium retaining potency of dren. The probability that most patients will experience
2 (Table I). Prednisone, prednisolone, and methylpred- iatrogenic complications with extended use underscores
nisolone are intermediate-acting agents and have less the clinician’s responsibility to inform patients of these
sodium retention than hydrocortisone. The long-acting potential outcomes. Many physicians request that patients
preparations are virtually devoid of sodium-retaining sign consent that these issues have been discussed before
activity and include dexamethasone, triamcinolone ace- therapy is initiated,but this practice is not universal.
tonide, fluticasone propionate, budesonide, and beta-
Immunophilin-binding agents
methasone dipropionate. Equivalent potencies and plasma
half-lives of the more important preparations are included Cyclosporine,tacrolimus,and sirolimus,derived from
in Table I. fungi, are important immunosuppressive medications
Giving GCS in multiple doses daily,such as every 6 to 8 that inhibit T-cell activation through a series of calcium-
hours, maximizes anti-inflammatory effects and adverse dependent signal events involved in cytokine gene tran-
side effects. Less effective (and less toxic) regimens scription. These compounds not only play especially
include single daily morning administration and alternate- important roles in suppression of solid organ allograft
S724 Nelson and Ballow J ALLERGY CLIN IMMUNOL
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TABLE II.Indications for the use of recombinant interferon in human illness
Interferon alpha-2a Interferon alpha-2b
Inteferon alpha-n Malignant melanoma,Condyloma acuminata
Malignant melanoma Follicular lymphoma
Follicular lymphoma AIDS-related Kaposi’s sarcoma
AIDS-related Kaposi’s sarcoma Condylomata acuminata
Condylomata acuminata Chronic hepatitis B
Chronic hepatitis C Chronic hepatitis C
Chronic myelogenous leukemia
Interferon beta-1b
Relapsing-remitting multiple sclerosis (ambulatory patients)
Interferon gamma
Chronic granulomatous disease
Idiopathic pulmonary fibrosis
Recurrent mycobacterium avium complex infection
rejection, they are the mainstays of GVHD prevention but a higher frequency of moderate to severe neurotoxic-
after HCT and are increasingly useful for the treatment of ity in liver transplant patients with hepatitis C.
autoimmune conditions. Sirolimus (rapamycin) is a macrocyclic lactone pro-
Cyclosporine (CsA) is a cyclic hexapeptide that blocks duced by Streptomyces hygroscopicis that inhibits, by a
the calcium-dependent signal-transduction pathway ema- distinctive mechanism,T-lymphocyte activation and pro-
nating from the T-cell receptor,thereby inhibiting the acti- liferation that occurs in response to antigenic and
vation of helper T cells. Tacrolimus (FK506) differs struc- cytokine stimulation. Sirolimus binds intracellularly to
turally from CsA but also interferes with T-cell receptor- the immunophilin, FK binding protein-12, which
dependent cell activation. Upon entry into the cells,these becomes an immunosuppressive complex. This complex
compounds form tight complexes with cytosolic receptors binds to and inhibits the activation of the mammalian
known as immunophilins, which subsequently bind to regulatory kinase, known as the target of rapamycin
calcineurin, inhibiting its phosphatase activity. This pre- (mTOR).27This inhibition suppresses cytokine-driven T-
vents the dephosphorylation and nuclear translocation of cell proliferation,inhibiting the progression from the G
1
the cytoplasmic subunit of the nuclear factor of activated to the S phases of the cell cycle. Sirolimus is indicated
T cells (NF-AT), rendering it incompetent. CsA and for the prophylaxis of organ rejection in patients receiv-
tacrolimus inhibit IL-2, IL-3, IL-4, INF-γ, granulocyte- ing renal transplants, and possibly as a treatment for
macrophage colony-stimulating factor, and TNF-α pro- steroid-refractory acute GVHD therapy.
duction. Transcriptional factors NF-AT, nuclear factor
kappaB (NF-κB),and PU-box are inhibited. T-cell recep- CYTOKINES
tor-mediated apoptosis of lymphocytes and thymocytes is Hematopoietic growth factors
augmented by tacrolimus but not CsA, which represents
an additional mechanism by which immunologic toler- Hematopoietic growth factors for clinical use,includ-
ance to allografts is achieved.22,23 ing erythropoietin,granulocyte colony stimulating factor,
CsA is used clinically to prevent GVHD after bone and granulocyte/monocyte colony stimulating factor,are
marrow transplantation and graft rejection of solid organ glycoproteins produced by recombinant DNA technolo-
transplants. CsA is also effective for the treatment of pso- gy. These compounds have revolutionized the treatment
riasis, ocular disease associated with Behcet’s disease, of iatrogenic anemia and leukopenia and have their most
endogenous uveitis,atopic dermatitis,rheumatoid arthri- widespread use in patients undergoing chemotherapy or
tis,Crohn’s disease,nephritic syndrome,aplastic anemia, transplantation for hematologic diseases and malignan-
pure red cell aplasia,polymyositis/dermatomyositis,pyo- cies, those with anemia associated with chronic renal
derma gangrenosum,and severe asthma.24-26Tacrolimus failure, and those requiring nucleoside analogue anti-
is used to promote solid organ tolerance,and clinical tri- retroviral therapy.28-31 Recently approved preparations
als for several autoimmune conditions are in progress. have longer durations of action that make weekly or even
The use of CsA and tacrolimus are complicated by the bimonthly administration possible.
fact that absorption can be somewhat erratic,blood levels
Interferons
need to be monitored,multiple drugs that are metabolized
by hepatic cytochrome p450 alter blood levels,and major Interferons for therapeutic use consist of recombinant
clinical toxicities exist. Adverse effects include nephropa- DNA products that are available for intramuscular, sub-
thy, hypertension, diabetes mellitus, susceptibility to cutaneous, intralesional, or intravenous injection.32 The
infection, development of malignancies, and posttrans- biological activities mimic those of the naturally occur-
plant lymphoproliferative disorder.27Tacrolimus is asso- ring endogenous molecules that are produced and secret-
ciated with less hypertension and less concomitant gluco- ed by white blood cells in response to viral infections and
corticosteroid requirement in renal transplant recipients, for immunologic activation. This family of molecules
J ALLERGY CLIN IMMUNOL Nelson and Ballow S725
VOLUME 111, NUMBER 2
TABLE III.Therapeutic antibodies and cytokine receptors for immunomodulation and immunotherapy
Therapeutic agent Proprietary Target Major indications Adverse effects
Polyclonal antibodies
Intravenous immunoglobulin Multiple* Organisms Immunodeficiencies Anaphylactoid
Fc receptors Post BMT
Idiotypes CLL
Pediatric AIDS
ITP
Kawaski Disease
Neurological diseases
Rh (D) immune globulin Rhogam D antigen Rh-neg mothers Minimal
Antithymocyte globulin Atgam Thymocytes Aplastic anemia Serum sickness
Thymoglobulin Organ rejection Opportunistic infection
Varicella-zoster VZIG Recently exposed subjects Modify course of disease Minimal
immune globulin
RSV immune globulin RSV-IGIV Respiratory-compromised Prevention during RSV Minimal except in
subjects season children with cyanotic
heart disease
Monoclonal antibodies
RSV monoclonal antibody Synagis Respiratory-compromised Prevention during RSV FDA approval pending
(palivizumab) subjects season
Muromonab-CD3 OKT3 CD3 lymphocytes Organ rejection Cytokine release
syndrome
Infliximab Remicade TNF-alpha RA,Crohn’s Lupus-like syndrome
Mycobacterial infection
Alemtuzumab Campeth-1H CD52+cells Refractory CLL Lymphopenia
Opportunistic infection
Rituximab Rituxin CD20+cells NHL Opportunistic Infection
Ibritumomab tiuxetan Zevulin CD20+cells Refractory NHL Opportunistic Infection
Omalizumab rhuMAb-25 IgE-Fc binding domain Steroid-dependent asthma Possible IgG antibodies
Cytokine receptors
Etanercept Enbrel TNF-alpha RA Injection site
soreness; bone marrow
suppression
Anakrina Non-glycosylated IL-1 RA Injection site
form of IL-1Ra soreness
Denileukin diftitox IL-2 No established dose
BMT,Bone marrow transplant;CLL,chronic lymphocytic leukemia;ITP,idiopathic thrombocytopenic purpura;RA,rheumatoid arthritis;NHL,non-Hodgkin’s
lymphoma.
*Multiple brands from different vendors.
was named for their capacity to “interfere”with in vitro orders, ischemic events, and infections. Some patients
infectivity of virions into mammalian cells. INF binds to with psoriasis experience disease exacerbations. Con-
the cell membrane and initiates a complex sequence of comitant administration of theophylline and interferon
intracellular events,which include induction of enzymes, alpha results in 100% increases in theophylline levels.
inhibition of cell proliferation,enhancement of phagocy-
IL-2
tosis by monocytes/macrophages, and augmentation of
specific cytotoxicity of lymphocytes for target cells.33 IL-2,described as a T-cell growth factor in 1976,stim-
These in vitro effects do not exactly correlate with clini- ulates growth of T lymphocytes from normal human bone
cal results; however, they correctly predict that these marrows.35,36The gene from IL-2 was discovered in 1983,
compounds modulate a wide array of clinical disease which made it possible for large-scale production by gene
immunopathophysiology. INF-α-2b, INF-β, and INF-γ expression in Escherichia coli; the product is biologically
have Food and Drug Administration-approved indica- and functionally similar to natural IL-2. Parenterally
tions for a number of proliferative conditions and viral administered IL-2 is associated with a broad array of mea-
infections, as listed in Table II.34 The administration of surable changes in immunologic function that are summa-
particular preparations is associated rarely with hyper- rized in a recent review.37 IL-2 is FDA-approved for
sensitivity reactions (eg, urticaria, angioedema, bron- metastatic renal cell carcinoma (RCC). Approximately
choconstriction, anaphylaxis). Common side effects 15% to 20% of patients experience an objective response
include fever, transient skin rashes, flulike symptoms, with therapy. The complete response rate is 5% to 7%,and
and bone marrow suppression. Thirty percent of patients about 80% of these complete responders will experience
experience neuropsychiatric symptoms,most commonly, response duration of greater than 2 years. Toxicity of
depression. Rarely,patients experience autoimmune dis- high–dose IL-2 therapy is significant,although treatment-
S726 Nelson and Ballow J ALLERGY CLIN IMMUNOL
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TABLE IV.Immunomodulatory mechanisms of action of IVIG
Fc receptor blockade or modulation
Fc receptor blockade of reticuloendothelial cell system and mononuclear phagocytes
Competitive interaction of IVIG with circulating IgG-sensitized platelets for Fc receptor on macrophages
Soluble Fcγreceptors compete with membrane Fc receptors (RES) for circulating IgG-sensitized platelets
Immunomodulation
Enhancement of T-cell suppressor function
Inhibition of B-cell function and/or antigen processing cells
Neutralization or binding of autoimmune antibodies by anti-idiotypic antibodies in the IVIG leading to restoration of idiotype-anti-
idiotypic network
Inhibition of complement uptake on target tissues; prevent complement-dependent immune damage to tissue and cells
Inhibition of cytokine/interleukin production/action
Neutralization of bacterial enterotoxin superantigens
Inhibition of Fas-mediated cell death by Fas blocking antibodies in the IVIG
related mortality of systemic IL-2 therapy is less than 1%. infection frequency.41Quartier and associates performed a
These toxicities include hypotension requiring pressors, retrospective study of the clinical features and outcomes of
major organ failure,myocardial infarction,and potentially 31 patients with X-linked agammaglobulinemia receiving
fatal systemic capillary leak.38 Fisher reported long-term replacement IVIG therapy between 1982 and 1997.42Early
follow-up of the original cohort of 255 RCC patients treat- treatment with IVIG and the achievement of a trough
ed with high-dose IL-2. The median response duration was serum IgG level of more than 500 mg/dL was effective in
54 months (range,3-131 months). The median duration for preventing severe acute bacterial infections; however,pul-
complete responders was not reached,but was greater than monary disease and sinusitis still occurred. The authors
or equal to 80 months (range,7-131 months). The median suggested that more intensive therapy to maintain a higher
survival time for all 255 patients was 16.3 months, with serum IgG level,for example,more than 800 mg/dL,may
10% to 20% estimated to be alive at 5 to 10 years after improve pulmonary outcome. The number of infections,
treatment.39 days missed from school or work, and hospitalized days
may not be sufficient indicators of adequate treatment.
THERAPEUTIC ANTIBODIES Therefore,the improvement or maintenance of pulmonary
function is an important measure of the success of therapy.
Intravenous immunoglobulin (polyclonal): Generally,it should take about 3 to 6 months after begin-
Immune replacement therapy and ning monthly IVIG infusions or a dosage change to reach
immunomodulation equilibration (steady state). For persons who have a high
catabolism of infused IgG, more frequent infusions—for
Immunoglobulin has been available for intravenous instance,every 2 to 3 weeks—of smaller doses may main-
administration since 1981, and this mode of therapy has tain the serum level in the normal range. The rate of elimi-
essentially replaced the use of intramuscular preparations nation of IgG may be higher during a period of active infec-
for the treatment of immunodeficiency diseases. Intra- tion. Measuring serum IgG levels and adjusting to higher
venous immunoglobulin (IVIG) is prepared by cold dosages or shorter intervals may be required.
ethanol-fractionation of plasma from multiple donors The risk of adverse reactions during the initial treat-
(10,000 to 60,000), followed by processes that remove ment is relatively high. Adverse effects are generally
antibody aggregates and inactivate potential viral associated with the presence of infections and formation
pathogens. Preparations are usually supplied as 5% or of immune complexes. In patients with active infection,
10% protein solutions. Ninety-five to 99% of the IVIG is the dose should be halved, that is, 200 mg/kg, and the
IgG, with trace amounts of IgA and IgM. IgG subclass dose repeated 2 weeks later to achieve a full dose. Treat-
distribution is similar to that of normal serum. Some prod- ment should not be discontinued. After achieving normal
ucts that contain very low amounts of IgA may be benefi- serum IgG levels, adverse reactions are uncommon
cial in patients with complete IgA deficiency and IgE unless patients have active infections. The most common
anti-IgA antibodies to minimize the risk of IgA sensitiza- side effects include flushing, headache, nausea, vomit-
tion and possible anaphylactic reactions.40 All current ing,and myalgias that are often infusion rate–dependent.
preparations are essentially equivalent and are selected on Severe anaphylactic episodes occur rarely in patients
the basis of cost,availability,and convenience,for exam- with IgE antibodies directed toward IgA.
ple,lyophilized versus a liquid form. Aseptic meningitis is a rare complication of IVIG,
Immune replacement therapy. IVIG is indicated as especially after large doses (1-2 g/kg), rapid infusions,
replacement therapy for patients with primary immunode- and the treatment of patients with autoimmune disorders
ficiency diseases who have deficient antibody production or inflammatory disease.43Pretreatment with aspirin (15
(Table III). Infusions are given every 3 to 4 weeks at a dose mg/kg/dose), acetaminophen (15 mg/kg/dose), diphen-
of 400 to 600 mg/kg to achieve a trough IgG level greater hydramine (1 mg/kg/dose), and/or hydrocortisone (6
than 500 mg/dL,a level that is correlated with reductions in mg/kg/dose, maximum 100 mg) 1 hour before the infu-
J ALLERGY CLIN IMMUNOL Nelson and Ballow S727
VOLUME 111, NUMBER 2
sion may prevent the adverse reactions.44 Acute renal Kazatchkine prepared F(ab)´ fragments from commer-
2
failure is a rare but significant complication of IVIG cial sources of IVIG that could neutralize or bind to
treatment, primarily in autoimmune patients receiving known autoantibodies,such as anti-factor VIII,anti-thy-
large doses of IVIG. IVIG containing sucrose as a stabi- roglobulin, anti-DNA, anti-intrinsic factor, and antineu-
lizer may confer greater risk for this renal failure. Risk trophil cytoplasmic antibodies (ANCA).54 Several
factors for this adverse reaction include pre-existing groups have reported that IVIG may be beneficial in the
renal insufficiency, diabetes mellitus, dehydration, age treatment of patients with ANCA-positive vasculitis who
older than 65, sepsis, paraproteinemia, and concomitant are refractory to conventional therapy.56
use of nephrotoxic agents. Monitoring blood urea nitro- Toxic epidermal necrolysis (TEN, or Lyell’s syn-
gen and creatinine before starting the treatment and peri- drome) is a severe drug-induced bullous skin reaction.
odically thereafter are necessary. The mortality rate can be up to 30%. Separation of large
One preparation was taken off the market after a series areas of the skin at the dermo-epidermal junction by
of cases of hepatitis C in 1994.45 Routine screening for apoptosis of keratinocytes results in epidermal detach-
hepatitis C RNA by reverse transcriptase-polymerase ment and the appearance of scalded skin. Viard and col-
chain reaction and the addition of a viral inactivation leagues reported that IVIG protected the keratinocytes
process in the final manufacturing step, for example, from apoptosis by blocking the effects of Fas ligand (L)
treatment with solvent/detergent, pasteurization, or both on the Fas receptor on keratinocytes. In an open,uncon-
has significantly reduced the risk of transmission of trolled trial IVIG (0.2-0.75 g/kg/day for 4 consecutive
hepatitis C and other viruses. There have been no reports days) was administered to 10 TEN patients. The skin pro-
of transmission of HIV or Creutzfeldt-Jakob disease in gression was halted within 1 to 2 days,followed by rapid
patients receiving IVIG replacement. skin healing and a favorable outcome.57 These
Immunomodulation. Since the first report by Imbach immunomodulating effects of IVIG in patients with TEN
et al on the use of IVIG in childhood autoimmune throm- represent another unique mechanism by which IVIG can
bocytopenia purpura (AITP),IVIG has been used for the modify the disease process. IVIG may be useful in other
treatment of a variety of inflammatory and autoimmune Fas-mediated inflammatory or autoimmune diseases.
disorders.46A number of mechanisms are postulated for IVIG has been shown to have a number of other
the immunomodulatory effects of IVIG (Table IV).47The immune-modulating effects. Sigman, et al reported that
mechanism of action for IVIG proposed for increasing high concentrations of IVIG, in a dose-dependent man-
the platelet counts in ITP is by blockade of the Fc recep- ner, inhibited in vitro IgE production.58 The inhibitory
tors on phagocytic cells in the reticuloendothelial sys- effect on IgE production was associated with a decrease
tems of the spleen and liver. This Fc receptor blockade in mRNA Cγtranscripts. IVIG also inhibited B-cell pro-
explains the rapid increase in platelet count after the liferation. IVIG may regulate IgE synthesis through the
administration of IVIG and leads to the prolonged sur- Fc receptor on B cells. This suppressive activity was
vival of autoantibody-coated platelets. Support for this dependent on the Fc portion of IVIG in that the F(ab)´
2
concept comes from the clinical studies of Debre et al,in fragments of IgG had no effect. IVIG can suppress the
which these investigators treated children with acute synthesis of various cytokines from monocytes. The
AITP with purified Fcγfragments prepared from IVIG.48 modulatory effects of IVIG on cytokine production may
Takei and coworkers reported that IVIG contains anti- be mediated through the Fcγ receptor on mononuclear
bodies to staphylococcal superantigen toxins that can cells and T cells.
block the T-cell stimulatory activities of these T-cell B cells and a subpopulation of T cells express a low
superantigens. IVIG contains antibodies to a broad range affinity Fcγ receptor (FcγRIIB). This receptor subtype
of staphylococcal and streptococcal enterotoxin.49It has provides an inhibitory signal to cells through a pathway
been proposed that a mechanism of IVIG,at least in part, mediated by an immunoregulatory tyrosine-based inhibi-
in Kawasaki disease is by neutralizing these bacterial tion motif (ITIM). Coligation of the B-cell receptor and
superantigen enterotoxins,blocking vascular endothelial FcγRIIB could be induced by the binding of IVIG
inflammation and damage.50 IVIG has also been useful through the Fc moiety of the IgG to the FcγRIIB recep-
in toxic shock syndrome if used during the early phases tor and the anti-idiotypic antibody specificity of the IgG
of the disease. Studies in animals and human disease molecule to the B-cell receptor.59Similar inhibitory Fcγ
show that IVIG can inhibit complement uptake on target receptors are present on basophils and mast cells.
cells. IVIG inhibits the binding of activated fragments of Samuelsson et al investigated a murine model of immune
C3 and C4 to target cells.51 Several reports by Dalakas thrombocytopenia. They found that the protective effects
and colleagues have shown that IVIG can reverse the of IVIG required the inhibitory Fc receptor,FcγRIIB,as
complement-mediated endomysial capillary damage in either disruption of the receptor or blocking with a mon-
patients with dermatomyositis.52,53Abnormalities in the oclonal antibody reversed the therapeutic effects.59Thus,
idiotype network have been postulated to be important in one mechanism by which IVIG may modulate B-cell
the pathophysiology of a number of autoimmune dis- immunoglobulin synthesis—and the immune effector
eases. The presence of anti-idiotypic antibodies in IVIG responses of other cell types that have this Fcγreceptor,
was first suggested by the response to IVIG therapy of a such as macrophages,mast cells,and others—is through
patient with autoimmunity to factor VIII.54,55 Rossi and the FcγRIIB receptor and its negative regulatory signal-
S728 Nelson and Ballow J ALLERGY CLIN IMMUNOL
FEBRUARY 2003
ing motifs. Probably no single mechanism accounts for and the hospitalized preterm infants (<28 weeks’gesta-
the immunoregulatory activities of IVIG; the immune- tion or ≤1000 g), regardless of maternal history. VZIG
modulating effects of IVIG are mediated by multiple can be obtained through the local American Red Cross
effects on various pathways of inflammatory and Blood Services. Immunocompromised children with no
immune effector responses. history of varicella,regardless of serologic results,prob-
ably should be given VZIG. Patients with primary
Polyclonal antibodies directed against cells
immune deficiency diseases receiving monthly high-dose
Rh (D) immune globulin is a human IgG globulin IVIG are likely to be protected and probably do not
solution containing an enriched fraction of antibodies require VZIG. VZIG is given by intramuscular injection.
against the D blood group antigen (Table III). When One vial containing 125 U is given for each kg of body
given to the Rh-negative mother within 72 hours of the weight. The suggested maximum dose is 625 U.
birth of an Rh-positive baby, the maternal antibody Respiratory syncytial virus-specific antibodies. Respi-
response to the Rh-positive cells from the fetus, which ratory syncytial virus (RSV) is a leading cause of lower
cross the placenta, can be suppressed. This represents respiratory illness in children. It is an important pathogen
one of the most effective and specific immunosuppres- in immunocompromised individuals, especially prema-
sive therapies available today and has prevented thou- ture infants,and children with chronic lung disease,con-
sands of cases of erythroblastosis fetalis, or hemolytic genital heart disease,multiple congenital anomalies,and
disease,of the newborn.60The rationale for immunosup- certain immunodeficiencies (Table III). Two approaches
pression in this setting is based on the fact that the pri- are available to prevent RSV infection in these at-risk
mary antibody response to the foreign D antigen is children: respiratory syncytial virus immune globulin
blocked by specific anti-D antibody administered pas- intravenous (RSV-IGIV),which is prepared from donors
sively at the time of exposure. selected for high serum titers of RSV neutralizing anti-
Antithymocyte globulin is a purified immunoglobulin body,and palivizumab,a humanized mouse-monoclonal
prepared from hyperimmune serum of horse, rabbit, antibody that is given intramuscularly.63Both agents are
sheep, or goat after immunization with human thymic approved for the prevention of RSV in children younger
lymphocytes (Table III). Intravenous administration than 24 months of age with bronchopulmonary dysplasia
results in binding to the surface of circulating T lympho- or with a history of premature birth (<35 weeks’gesta-
cytes, resulting in lymphopenia and profound suppres- tion). RSV-IGIV is given monthly throughout the RSV
sion of cellular immune responses. The half-life is season at a dose of 15 mL/kg (750 mg/kg). Palivizumab
between 3 and 9 days. Major toxicities include serum is administered intramuscularly in a dose of 15 mg/kg
sickness and nephritis. It is used for the treatment of idio- once a month during the RSV season. Palivizumab is pre-
pathic aplastic anemia and acute rejection of solid organ ferred for most high-risk children because of its ease of
renal and cardiac transplants.61 administration, safety, and effectiveness. Patients with
severe chronic lung disease may benefit from RSV pro-
Hyperimmune globulins (polyclonal and
phylaxis for two seasons, especially those who have
monoclonal) for infectious diseases
ongoing medical problems. RSV-IGIV is contraindicated
Specific immune globulins,also called “hyperimmune in children with cyanotic heart disease. In contract,
globulins,” are prepared from select donors who have palivizumab is pending approval before the Food and
high titers of the desired antibody, either naturally Drug Administration for the use in children with cyanot-
acquired or stimulated through immunization. Samples ic congenital heart disease.
of specific immune globulins for use in the passive pro-
Monoclonal antibodies as
tection of infectious diseases include hepatitis B immune
immunomodulators
globulin,rabies immune globulin,tetanus immune glob-
ulin, varicella-zoster immune globulin, cytomegalovirus Muromonab-CD3 is a murine monoclonal antibody to
immunoglobulin intravenous, and respiratory syncytial the CD3 antigen of human T cells (Table III). It is a bio-
virus immune globulin intravenous. logically purified IgG2a immunoglobulin that is directed
Varicella-zoster virus (VZV) polyclonal. Varicella- against a glycoprotein on the surface of human T-cell
zoster immune globulin (VZIG) is used to prevent or marker CD3,which is associated in vitro with the antigen
modify the course of varicella, but is not effective once recognition structure of T cells that is essential for signal
the disease is established.62 VZIG should be adminis- transduction. In vivo, there is a rapid decrease in circu-
tered as soon as possible,and no later than 96 hours after lating CD3+CD8+and CD3+CD4+cells,which are unde-
exposure (Table III). Provided significant exposure has tectable in the peripheral blood from 2 and 7 days after
occurred, potential candidates for VZIG include infusion. Patients develop neutralizing antibodies with
immunocompromised children without a history of repeated treatment that abrogates some of this activity.
chickenpox, susceptible pregnant women, newborn Muromonab-CD3 is approved for the treatment of acute
infants whose mother had onset of chickenpox within 5 allograft rejection in renal transplant recipients and for
days before delivery or 48 hours after delivery,hospital- GCS-resistant acute allograft rejection of heart and liver
ized premature infants (≥28 weeks’ gestation) whose transplants.64 Most patients experience acute clinical
mother has no history of chickenpox and is seronegative, syndrome (cytokine release syndrome) associated with
J ALLERGY CLIN IMMUNOL Nelson and Ballow S729
VOLUME 111, NUMBER 2
the initial dose of muromonab-CD3; manifestations An alternative monoclonal anti-CD20, ibritumomab,
range from a flu-like illness to capillary leak, hypoten- has been linked to the isotope yttrium-90 using tiuxetan
sion,and multiorgan failure. (a linker chelator) to create a radioimmunotherapy
Infliximab is an IgG1k monoclonal antibody that is agent.69 Ibritumomab tiuxetan, the first radioim-
chimeric (human constant and murine variable regions). It munotherapy to gain FDA sanction (February 2002), is
binds specifically and with high affinity to TNF-α(Table useful for the treatment of patients with relapsing or
III). TNF-α induces IL-1 and IL-6, promotes leukocyte refractory low-grade, follicular, or transformed B-cell
migration, activates neutrophils and eosinophils, and non-Hodgkin’s lymphoma. The addition of a radionu-
induces acute phase reactant production and tissue degrad- clide appears to boost the antibody therapy response rate
ing enzymes.65Infliximab is an important addition to the by combining the specificity of the antibody with the
therapeutic treatments of patients with rheumatoid arthri- cytotoxic impact of molecular radiotherapy, when used
tis and is used in conjunction with methotrexate. It is also in a dosing schedule that includes unlabeled rituximab
indicated for patients with Crohn’s disease who experience and follows a two-stage approach. Eighty percent of
an inadequate response to conventional therapy. Side patients responded in a multicenter study (30% achieved
effects include autoantibody production and a lupuslike a complete response), leading to fast-track approval
syndrome,acute infusion reactions,infections,and possi- using this approach.70 Other monoclonal antibodies are
ble increased incidence of malignancy. seeing their way into the clinic, including humanized
Alemtuzumab is a recombinant DNA-derived anti-CD25, which is used to treat certain selected T-cell
humanized monoclonal antibody (Campeth-1H) that is malignancies and post-solid organ transplant rejection,
directed against the 21-28 Kd cell surface protein, and is being evaluated in certain autoimmune diseases.
which is expressed on the surface of normal and malig- Omalizumab is a humanized murine monoclonal anti-
nant B and T lymphocytes, NK cells, monocytes, body (rhuMAb-E25) specific for the Fc-binding domain
macrophages,and tissues of the male reproductive sys- of IgE (Table III). This anti-IgE monoclonal antibody has
tem (Table III).66 CD52 is not present on erythrocytes been tested in allergic asthmatic subjects and was shown
or hematopoietic stem cells. Alemtuzumab is indicated to suppress both early- and late-phase responses to
for the treatment of B-cell chronic lymphocytic inhaled allergen.71When omalizumab was tested against
leukemia in patients who have been treated with alky- placebo in a 20-week trial of steroid-dependent allergic
lating agents and who have failed fludarabine therapy.67 asthmatic subjects, asthma and steroid-use scores
The broad array of immune cells that carry the CD52 decreased significantly.72This and other anti-IgE mono-
receptor predict that the immunosuppressive properties clonal antibodies being proposed for human use may
in patients are more profound than that seen with mon- prove useful in moderate to severe asthma. A note of cau-
oclonal directed at more “selective” receptors. Alem- tion was sounded by the observation that inhaled anti-IgE
tuzumab produces a profound lymphopenia that is asso- generated IgG anti-rhuMAb-E25 antibodies.73 The
ciated with the development of opportunistic infections. mechanism of action of rhuMAb-E25 is thought to be the
Anti-infective prophylaxis is recommended upon initia- competition of the molecule for free IgE’s Fc region,thus
tion of therapy and for a minimum of 2 months after the preventing the free IgE from binding to the mast cell sur-
last dose or until absolute CD4+cell numbers are high- face IgE receptor through its Fc region.
er than 200 cells/mm3. The median time to recovery to
greater than 200 cells/mm3 is 2 months; however, the CYTOKINE RECEPTOR INHIBITORS
baseline CD4+ cell number may not be reached for 12 Soluble TNF receptor
months. Life-threatening bone marrow aplasia has also
occurred in some patients treated with recommended TNF is an important proinflammatory cytokine that
dosages. Clinical trials are ongoing,using this antibody plays a role in the pathogenesis of rheumatoid arthritis.
as GVHD prophylaxis and as a conditioning therapy Immune-modifying agents, which inhibit the activity of
prior to nonablative HCT. TNF,are available for the treatment of several inflamma-
Rituximab is a chimeric human/murine monoclonal tory diseases including rheumatoid arthritis (Table III).
antibody against the cell surface antigen CD20 of nor- Etanercept (Enbrel) is a genetically engineered fusion
mal and malignant B lymphocytes (Table III). Intra- protein consisting of two identical chains of recombinant
venous administration of rituximab in humans results in human TNF-receptor p75 monomer fused with the Fc
a disappearance of B cells from the circulation for weeks domain of human IgG .74 This soluble fusion protein
1
to months, depending on the dosing schedule. CD20 is binds and inactivates TNF,thereby competing with cell-
expressed on more than 90% of non-Hodgkin’s lym- bound TNF-receptors for free TNF. Several randomized,
phomas and mature normal B cells but not hematopoiet- double-blind, placebo-controlled trials have shown that
ic cells, pro-B cells, normal plasma cells, or other nor- Etanercept treatment can lead to significant clinical ben-
mal tissues. It is approved for the treatment of patients efit with minimal toxicity in patients with rheumatoid
with relapsed or refractory, low-grade, or follicular arthritis who have had an inadequate response to other
CD20-positive,B-cell non-Hodgkin’s lymphoma.68It is disease-modifying drugs. A trial in adults of the addition
also being evaluated for the treatment of several autoim- of methotrexate to Etanercept therapy resulted in rapid
mune conditions. and sustained improvement in rheumatoid arthritis