Lymphocyte Immunization Therapy (LIT) in Reproductive Failures: New Horizons

150 Pages·2022·4.003 MB·English

by  Mohan Raut, Mugdha Raut

Mohan Raut
Mugdha Raut
Lymphocyte
Immunization
Therapy (LIT) in
Reproductive
Failures
New Horizons
Lymphocyte Immunization Therapy (LIT)
in Reproductive Failures
(cid:129)
Mohan Raut Mugdha Raut
Lymphocyte
Immunization Therapy
(LIT) in Reproductive
Failures
New Horizons
MohanRaut MugdhaRaut
Dr.Raut’sCentreforReproductive Dr.Raut’sCentreforReproductive
Immunology Immunology
Mumbai,India Mumbai,India
ISBN978-981-19-2959-5 ISBN978-981-19-2960-1 (eBook)
https://doi.org/10.1007/978-981-19-2960-1
#SpringerNatureSingaporePteLtd.2022
Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeorpartofthe
materialisconcerned,specificallytherightsoftranslation,reprinting,reuseofillustrations,recitation,
broadcasting,reproductiononmicrofilmsorinanyotherphysicalway,andtransmissionorinformation
storageandretrieval,electronicadaptation,computersoftware,orbysimilarordissimilarmethodology
nowknownorhereafterdeveloped.
Theuseofgeneraldescriptivenames,registerednames,trademarks,servicemarks,etc.inthispublication
doesnotimply,evenintheabsenceofaspecificstatement,thatsuchnamesareexemptfromtherelevant
protectivelawsandregulationsandthereforefreeforgeneraluse.
The publisher, the authors and the editors are safe to assume that the advice and information in this
bookarebelievedtobetrueandaccurateatthedateofpublication.Neitherthepublishernortheauthorsor
theeditorsgiveawarranty,expressedorimplied,withrespecttothematerialcontainedhereinorforany
errorsoromissionsthatmayhavebeenmade.Thepublisherremainsneutralwithregardtojurisdictional
claimsinpublishedmapsandinstitutionalaffiliations.
ThisSpringerimprintispublishedbytheregisteredcompanySpringerNatureSingaporePteLtd.
The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721,
Singapore
Thisbookisdedicatedtoourteacher,mentor,
friend, philosopher, and guide
Dr. Usha Krishna.
We would not be where we are today, in the
field of reproductive immunology, without
her.
Preface
This is the first-ever book to be written on alloimmune aspects in “unexplained”
repeatedpregnancyloss(RPL),recurrentimplantationfailure(RIF),andtheroleof
lymphocyteimmunizationtherapy(LIT)intheseconditions.
Pregnancy is a unique condition where the embryo/fetus grows in an immuno-
logicallydifferentenvironmentofthemotherwithoutanyimmunereactionagainst
it. The fetus actually is a “semiallograft,” meaning it enjoys special status in the
mother’s body. This “paradox of pregnancy” has intrigued biologists,
immunologists, reproductive immunologists, physicians, and obstetricians for
decades. And over the years, many theories have been proposed to explain this
complex phenomenon. Clinical research is now being combined with ongoing
researchinreproductiveimmunologytounderstandthemechanismbehindsuccess-
fulpregnancies.Thisisimportantbecausenowithasbeenestablishedthatincouples
with unexplained RPL/RIF, alloimmune incompatibility plays an important causa-
tiverole.Itisfoundthatinmorethan50%ofRPLandRIFcases,thepossiblereason
could bethealloimmune rejection ofpregnancy.Numerous studies havealso been
done to examine the impact of different immunomodulatory treatments on the
managementofRPL/RIF.
LIT is the first and most popular immunomodulation modality. It has been
extensivelyresearchedandrecommendedallaroundtheglobe,andmultiplestudies
have demonstrated the effectiveness. In fact, it was also one of the first treatments
recommendedforuRPL/uRIF.
A big reason to write this book was the lack of awareness about this excellent
method of treatment called LIT. This book aims to inform about how LIT was
developed, the mechanisms through which LIT acts, and the procedure to perform
LIT. Since LIT has been surrounded by different controversies from time to time,
thereareimportantchaptersinthisbookwhichcleartheairaround themandtalks
aboutthelatestmeta-analysesthatprovetheefficacyofLIT.
WehavealsosharedreviewsofvariousstudiesrelatedtoLIT,conductedoverthe
last20years,whichwillhelpreadersunderstandLITbetter.Thebookalsoaddresses
the most important dilemma to clinicians, which is the diagnosis of alloimmune
factors.Wehavetalkedaboutthevariousteststhatareofferedforthediagnosis.Our
associationwithLITstartedin1991,whenDr.Mohanwasapartofthemulticentric
double-blindstudyontheroleofLITinRPL,conductedbyNuffieldDepartmentof
vii
viii Preface
Obstetrics (Prof. Redman), Oxford. Now, we are doing LITs at our center—Dr.
Raut’s Centre for Reproductive Immunology, in Mumbai, India, with a patented
process.
WehopethatthisbookwillhelpreadersinunderstandingLITbetterandclearthe
doubts and uncertainties associated with the procedure. We truly believe that
research is an integral part of science, and it contributes greatly to the progress of
science.Reproductiveimmunologyisanever-expandingfield,andwewillwitness
moreresearchinthisfieldinthefuture.Itisveryimportanttoconvertthisresearch
intoclinicalpracticesothatitcanhelpmankind.WearealsosurethatLITwillalso
seemanyupgradeswithcontinuousresearch,anditwillhelpanincreasingnumber
of couples who are suffering from the unfortunate problem of “unexplained”
RPL/RIF,andtheywillbeabletofulfilltheirdreamofhavingtheirbaby.
As the process of LIT is under patent protection, all the details could not be
revealed in the book, but all procedures and facts are discussed, along with their
safetyregulations.Towardstheend,therearecasestudiesoftheLITprocessandour
thoughtsonthefutureofLIT.
Mumbai,India MohanRaut
Mumbai,India MugdhaRaut
Acknowledgments
It is our privilege to announce that Lymphocyte Immunization Therapy (LIT) in
ReproductiveFailures:NewHorizonsisthefirstbookexclusivelydedicatedtothe
subject of Lymphocyte Immunization Therapy (LIT). We have received help,
support,and encouragementfrom a lot ofpeople.We appreciate andacknowledge
allofthemfromthebottomofourhearts.
However, there are some who deserve a special mention, and our expression of
gratitudewillnotbecompletewithoutthat.
We would like to extend our deepest gratitude to Dr. Usha Krishna, because of
whomwewereintroducedtothefieldofReproductiveImmunology.Shehasguided
us throughout our journey in this field and in setting up of our Reproductive
Immunologycenter.
We would like to express our deepest thanks to Dr. O. B. Christiansen,
ex-secretaryandcurrentlyCouncilor,EuropeanSocietyforReproductiveImmunol-
ogy.HehadinauguratedourReproductiveImmunologycenterinMumbaiandthat
pavedthewayforourworkrelatedtoLIT,whichhasnowculminatedintothisbook.
WewouldliketothankDr.JoanneKwak-Kim,pastpresident,AmericanSociety
forReproductiveImmunology,forherconstantencouragementinourworkrelated
toLIT.
The concept of this book came into existence due to the suggestions of
Dr. Abhinav Shrestha Jha, ex-associate editor, Springer Nature, and an immunolo-
gist.Wewouldliketopayourspecialregardstohimforthat.
This book would not have been completed without the help of our daughters,
Adv. Nupur, who practices law in Delhi, and Natasha, molecular biology and data
science student from UC Berkeley. We would like to recognize their invaluable
assistanceinthisventurewithaspecialthankstothem.
WeareverygratefultoMr.PiyushBhatiaandhisteamfortheirtimelyhelp.
WearealsothankfultotheSpringerNatureteam,especiallyDr.BhavikSawhney
(Associateeditor—biomedicine)andMr.KumarAthiappan(ProjectCoordinator—
Books),fortheirhelpwithalotofpatience!
In the end, we would like to express our gratitude to our teachers, parents,
patients,well-wishers,andtheAlmighty!
ix
Contents
PartI ReproductiveImmunologyandReproductiveFailure
(RepeatedPregnancyLoss/RecurrentImplantation
Failure/UnexplainedInfertility)
1 IntroductiontoReproductiveImmunologyandReproductive
Failure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Reference. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
2 RecurrentPregnancyLossandRecurrentImplantationFailure. .. 5
2.1 RecurrentPregnancyLoss. . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2.1.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2.1.2 Definitions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
2.1.3 BiochemicalPregnancyandRPL. . . . . . . . . . . . . . . 6
2.1.4 DiagnosticCriteriaforRPLDefinition. . . . . . . . . . . 7
2.1.5 RPLAttributabletoChance.. . . .. . . .. . . . .. . . .. 7
2.1.6 TypesofRPLbyEtiology. . . . . . . . . . . . . . . . . . . . 8
2.1.7 TypesofUnexplainedRPL(SeeTable2.3)[13]. . . . 8
2.1.8 Incidence. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
2.2 RecurrentImplantationFailure. . . . . . . . . . . . . . . . . . . . . . . . 9
2.2.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
2.2.2 Definitions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
2.2.3 RIFVersusRecurrentIVFFailure. . . . . . . . . . . . . . 10
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
3 ImmuneSystem. . . . . . . .. . . . . . .. . . . . . . .. . . . . . . .. . . . . . . .. 15
3.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
3.1.1 Recognition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
3.1.2 Response. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
3.2 TypesofImmunity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
3.2.1 InnateImmunity. . . . . . . . . . . . . . . . . . . . . . . . . . . 17
3.2.2 AdaptiveImmunity. . . . . . . . . . . . . . . . . . . . . . . . . 19
3.3 TheCellsoftheImmuneSystem. . . . . . . . . . . . . . . . . . . . . . 20
3.4 Lymphocytes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
3.4.1 NaïveandEffectorLymphocytes. . . . . . . . . . . . . . . 22
xxii
xii Contents
3.4.2 BLymphocytes(BCells). . . . . . . . . . . . . . . . . . . . 22
3.4.3 TLymphocytes(TCells). . . . . . . . . . . . . . . . . . . . 23
3.4.4 NaturalKillerCells. . . . . . . . . . . . . . . . . . . . . . . . . 24
3.4.5 NKTCell. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
3.5 MononuclearPhagocytes. . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
3.6 MajorHistocompatibilityComplex. . . . . . . . . . . . . . . . . . . . . 27
3.6.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
3.6.2 Structure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
3.6.3 Function. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
3.7 Cytokines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
3.7.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
3.7.2 Functions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
3.7.3 Types. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
3.7.4 Importance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
4 ImmunologyofPregnancy(ReproductiveImmunology). . . . . . . . . 31
4.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
4.2 FetusasAllograft. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
4.3 ImmuneResponseinNormalPregnancy. . . . . . . . . . . . . . . . . 32
4.4 MechanismsofImmunoprotectionofEmbryo. . . . . . . . . . . . . 36
4.5 MechanismsofAlloimmuneRejectionofPregnancy. . . . . . . . 36
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
5 DiagnosisofAlloimmuneFactor. . . . . . . . . . . . . . . . . . . . . . . . . . . 39
5.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
5.2 LevelOne. . .. . . . .. . . . .. . . . .. . . . .. . . . .. . . . .. . . . .. 41
5.2.1 TestforGeneticFactors. . . . . . . . . . . . . . . . . . . . . 41
5.2.2 TestforAnatomicalFactors. . . . . . . . . . . . . . . . . . 42
5.2.3 TestforEndocrineFactors. . . . . . . . . . . . . . . . . . . 42
5.2.4 TestforInfections. . . . . . . . . . . . . . . . . . . . . . . . . 42
5.2.5 TestforAutoimmunity. . . . . . . . . . . . . . . . . . . . . . 43
5.2.6 TestforThrombophilia. . . . . . . . . . . . . . . . . . . . . . 43
5.2.7 OtherTests. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
5.3 LevelTwo. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
5.3.1 LymphocyteCrossmatch. . . . . . . . . . . . . . . . . . . . . 44
5.3.2 PeripheralBloodNKCells(pNKCells). . . . . . . . . . 45
5.3.3 UterineNKCells. . . . . . . . . . . . . . . . . . . . . . . . . . 47
5.3.4 SerumTNF-alpha. . . . . . . . . . . . . . . . . . . . . . . . . . 49
5.3.5 HLADQ-alphaGenotype. . . . . . . . . . . . . . . . . . . . 50
5.3.6 T-regCellEstimation(CD4+CD25+foxP3). . . . . . . 50
5.3.7 TH1-TH2IntracellularCytoplasmicRatio. . . . . . . . 51
5.3.8 KIRGenotyping. . . . . . . . . . . . . . . . . . . . . . . . . . . 52
5.3.9 CD4/CD8Ratio. . . . . . . . . . . . . . . . . . . . . . . . . . . 53
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53