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Immunologic Basis of Graft Rejection
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Clinical Manifestations of Graft Rejection
s
General Immunosuppressive Therapy
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Specific Immunosuppressive Therapy
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Immune Tolerance to Allografts
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Clinical Transplantation
Transplantations Routinely Used in Clinical Practice
TransplantationImmunology
T
,
immunology,refers to the act oftransferring cells,tissues,or organs from one site to another.Thedesire to accomplish transplants stems from the realizationthat many diseases can be cured by implantation ofa healthyorgan,tissue,or cells (a graft) from one individual (thedonor) to another in need ofthe transplant (the recipient orhost).The development ofsurgical techniques that allow thefacile reimplantation oforgans has removed one barrier tosuccessful transplantation,but others remain.One is the lack oforgans for transplantation.Although a supply oforgans isprovided by accident victims and,in some cases,livingdonors,there are more patients in need oftransplants thanthere are organs available.The seriousness ofthe donor-organ shortage is reflected in the fact that,as ofNovember2000,an estimated 73,000 patients in the United States wereon the waiting list for an organ transplantation.The major-ity ofthose on the list (~70%) require a kidney;at present,the waiting period for this organ averages over 800 days.While the lack oforgans for transplantation is a serious is-sue,the most formidable barrier to making transplantationa routine medical treatment is the immune system.Theimmune system has evolved elaborate and effective mecha-nisms to protect the organism from attack by foreign agents,and these same mechanisms cause rejection ofgrafts fromanyone who is not genetically identical to the recipient.Alexis Carrel reported the first systematic study oftrans-plantation in 1908;he interchanged both kidneys in a seriesofnine cats.Some ofthose receiving kidneys from other catsmaintained urinary output for up to 25 days.Although allthe cats eventually died,the experiment established that atransplanted organ could carry out its normal function inthe recipient.The first human kidney transplant,attemptedin 1935 by a Russian surgeon,failed because there was a mis-match ofblood types between donor and recipient.Thisincompatibility caused almost immediate rejection ofthekidney,and the patient died without establishing renal func-tion.The rapid immune response experienced here,termedhyperacute rejection,is mediated by antibodies and will bedescribed in this chapter.The first successful human kidneytransplant,which was between identical twins,was accom-plished in Boston in 1954.Today,kidney,pancreas,heart,lung,liver,bone-marrow,and cornea transplantations areperformed among nonidentical individuals with ever-increasing frequency and success.A variety ofimmunosuppressive agents can aid in thesurvival ofthe transplants,including drugs and specific anti-bodies developed to diminish the immunologic attack ongrafts,but the majority ofthese agents have an overallimmunosuppressive effect,and their long-term use is delete-rious.New methods ofinducing specific tolerance to thegraft without suppressing other immune responses are beingdeveloped and promise longer survival oftransplants with-out compromise ofhost immunity.This chapter describesthe mechanisms underlying graft rejection,various proce-dures that are used to prolong graft survival,and a summaryofthe current status oftransplantation as a clinical tool.AClinical Focus section examines the use oforgans from non-human species (xenotransplants) to circumvent the shortageoforgans available for patients in need ofthem.
chapter
21
Immunologic Basis of Graft Rejection
The degree ofimmune response to a graft varies with thetype ofgraft.The following terms are used to denote differ-ent types oftransplants:
s
Autograft
is self-tissue transferred from one body site toanother in the same individual.Transferring healthy skinto a burned area in burn patients and use ofhealthyblood vessels to replace blocked coronary arteries areexamples offrequently used autografts.
s
Isograft
is tissue transferred between genetically identicalindividuals.In inbred strains ofmice,an isograft can beperformed from one mouse to another syngeneic mouse.In humans,an isograft can be performed betweengenetically identical (monozygotic) twins.
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Allograft
is tissue transferred between geneticallydifferent members ofthe same species.In mice,anallograft is performed by transferring tissue or an organfrom one strain to another.In humans,organ grafts fromone individual to another are allografts unless the donorand recipient are identical twins.
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Xenograft
is tissue transferred between different species(e.g.,the graft ofa baboon heart into a human).Becauseofsignificant shortages in donated organs,raisinganimals for the specific purpose ofserving as organdonors for humans is under serious consideration.Autografts and isografts are usually accepted,owing to thegenetic identity between graft and host (Figure 21-1a).Be-cause an allograft is genetically dissimilar to the host,it isoften recognized as foreign by the immune system and is re- jected.Obviously,xenografts exhibit the greatest genetic dis-parity and therefore engender a vigorous graft rejection.
Allograft Rejection Displays Specificityand Memory
The rate ofallograft rejection varies according to the tissueinvolved.In general,skin grafts are rejected faster than othertissues such as kidney or heart.Despite these time differ-ences,the immune response culminating in graft rejectionalways displays the attributes ofspecificity and memory.Ifaninbred mouse ofstrain A is grafted with skin from strain B,primary graft rejection,known as first-set rejection,occurs(Figure 21-1b).The skin first becomes revascularized betweendays 3 and 7;as the reaction develops,the vascularized trans-plant becomes infiltrated with lymphocytes,monocytes,neu-trophils,and other inflammatory cells.There is decreased vas-cularization ofthe transplanted tissue by 7–10 days,visiblenecrosis by 10 days,and complete rejection by 12–14 days.Immunologic memory is demonstrated when a secondstrain-B graft is transferred to a previously grafted strain-Amouse.In this case,a graft-rejection reaction develops morequickly,with complete rejection occurring within 5–6 days;this secondary response is designated second-set rejection(Figure 21-1c).The specificity ofsecond-set rejection can bedemonstrated by grafting an unrelated strain-C graft at thesame time as the second strain-B graft.Rejection ofthestrain-C graft proceeds according to first-set rejection kinet-ics,whereas the strain-B graft is rejected in an acceleratedsecond-set fashion.
T Cells Play a Key Role in Allograft Rejection
In the early 1950s,Avrion Mitchison showed in adoptive-transfer experiments that lymphocytes,but not serum anti-body,could transfer allograft immunity.Later studies im-plicated T cells in allograft rejection.For example,nudemice,which lack a thymus and consequently lack functionalT cells,were found to be incapable ofallograft rejection;indeed,these mice even accept xenografts.In other studies,T cells derived from an allograft-primed mouse were shownto transfer second-set allograft rejection to an unprimedsyngeneic recipient,as long as that recipient was grafted withthe same allogeneic tissue (Figure 21-2).Analysis ofthe T-cell subpopulations involved in allograftrejection has implicated both CD4
+
and CD8
+
populations.In one study,mice were injected with monoclonal antibodiesto deplete one or both types ofT cells and then the rate of graft rejection was measured.As shown in Figure 21-3,re-moval ofthe CD8
+
population alone had no effect on graftsurvival,and the graft was rejected at the same rate as in con-trol mice (15 days).Removal ofthe CD4
+
T-cell populationalone prolonged graft survival from 15 days to 30 days.How-ever,removal ofboth the CD4
+
and the CD8
+
T cells resultedin long-term survival (up to 60 days) ofthe allografts.Thisstudy indicated that both CD4
+
and CD8
+
T-cells partici-pated in rejection and that the collaboration ofboth subpop-ulations resulted in more pronounced graft rejection.
Similar Antigenic Profiles FosterAllograft Acceptance
Tissues that are antigenically similar are said to be
histocom-patible;
such tissues do not induce an immunologic responsethat leads to tissue rejection.Tissues that display significantantigenic differences are
histoincompatible
and induce animmune response that leads to tissue rejection.The variousantigens that determine histocompatibility are encoded bymore than 40 different loci,but the loci responsible for themost vigorous allograft-rejection reactions are located with-in the
major histocompatibility complex (MHC).
The orga-nization ofthe MHC—called the H-2 complex in mice andthe HLA complex in humans—was described in Chapter 7(see Figure 7-1).Because the MHC loci are closely linked,they are usually inherited as a complete set,called a
haplo-type,
from each parent.
482
PART IV
The Immune System in Health and Disease
Within an inbred strain ofmice,all animals are homozy-gous at each MHC locus.When mice from two different in-bred strains,with haplotypes
b
and
k,
for example,are mated,all the F
1
progeny inherit one haplotype from each parent (seeFigure 7-2a).These F
1
offspring have the MHC type
b/k
andcan accept grafts from either parent.Neither ofthe parentalstrains,however,can accept grafts from the F
1
offspring be-cause each parent lacks one ofthe F
1
haplotypes.MHC inher-itance in outbred populations is more complex,because thehigh degree ofpolymorphism exhibited at each MHC locus
Transplantation Immunology
CHAPTER
21
483
VISUALIZING CONCEPTS
(a) Autograft acceptanceGrafted epidermisBlood vesselsDays 3–7: Revascularization(b) First-set rejectionGrafted epidermis(c) Second-set rejectionGrafted epidermisDays 3–7: RevascularizationDays 3–4: Cellular infiltrationMediatorsDays 7–10: HealingNeutrophilsDays 12–14: ResolutionDays 10–14: Thrombosis and necrosisDamaged blood vesselsBloodclotsNecrotic tissueDays 7–10: Cellular infiltrationDays 5–6: Thrombosis and necrosisNecrotic tissueBlood clots
FIGURE
21-1
Schematic diagrams of the process of graft ac-ceptance and rejection. (a) Acceptance of an autograft is com-pleted within
12–14
days. (b) First-set rejection of an allograftbegins
7–10
days after grafting, with full rejection occurring by
10–14
days. (c) Second-set rejection of an allograft begins within
3–4
days, with full rejection by
5–6
days. The cellular infiltrate thatinvades an allograft (b, c) contains lymphocytes, phagocytes, andother inflammatory cells.
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Capitol 21 Transplant
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