introductory immunology || transplantation immunology

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CHAPTER 11 11 Transplantation Immunology Chapter Focus: To examine immune regulation of transfer, or grafting, of tissues from one person to another. Transplanted organs have the potential to be rejected by the hosts immune system unless the recipi- ent is either tolerant or immunosuppressed. Concepts associated with mechanisms underlying the immunobiology of transplantation will be discussed. The goals are to present genetic relationships between indivi- duals that are critical for transplantation and to categorize immune- mediated events between donor and host post-transplant. Mechanisms will be defined, with details on the contributing cells and factors involved in transplant acceptance vs. rejection. Rejection topics will be discussed, including graft-versus-host disease (GVHD). Finally, classes of immunosuppressive agents will be presented to assess therapeutic intervention as a way to control immune features that affect graft acceptance and rejection. TRANSPLANTATION DEFINED The concept of organ replacement has become an important part of modern medical therapy. It has been known experimentally that skin can be transferred to different sites on the same person, with great success. This is referred to as an autograft; all molecules are identical within the individual and the syngeneic tissue is recognized as self.However, tissues transferred between nonrelated individuals (allograft) are not readily tolerated; their cellular components are recognized as foreign antigens. Immune responses are initiated within the recipient to eliminate the foreign tissue. Likewise, tissues from nonrelated species (xenograft or heterograft) share a similar fate and are rapidly rejected unless a high degree of immunosuppression is present. The rules that govern graft acceptance and rejection, and the immu- nological basis of successful graft acceptance, are well defined (Figure 11.1). Introductory Immunology. DOI: http://dx.doi.org/10.1016/B978-0-12-420030-2.00011-1 Copyright © 2014 Elsevier Inc. All rights reserved.

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Page 1: Introductory Immunology || Transplantation Immunology

CHAPTER 1111Transplantation Immunology

Chapter Focus: To examine immune regulation of transfer, or grafting,of tissues from one person to another. Transplanted organs have thepotential to be rejected by the host’s immune system unless the recipi-ent is either tolerant or immunosuppressed. Concepts associated withmechanisms underlying the immunobiology of transplantation will bediscussed. The goals are to present genetic relationships between indivi-duals that are critical for transplantation and to categorize immune-mediated events between donor and host post-transplant. Mechanismswill be defined, with details on the contributing cells and factorsinvolved in transplant acceptance vs. rejection. Rejection topics will bediscussed, including graft-versus-host disease (GVHD). Finally, classesof immunosuppressive agents will be presented to assess therapeuticintervention as a way to control immune features that affect graftacceptance and rejection.

TRANSPLANTATION DEFINED

The concept of organ replacement has become an important part ofmodern medical therapy. It has been known experimentally that skincan be transferred to different sites on the same person, with greatsuccess. This is referred to as an autograft; all molecules are identicalwithin the individual and the syngeneic tissue is recognized as “self.”However, tissues transferred between nonrelated individuals (allograft)are not readily tolerated; their cellular components are recognized asforeign antigens. Immune responses are initiated within the recipientto eliminate the foreign tissue. Likewise, tissues from nonrelatedspecies (xenograft or heterograft) share a similar fate and are rapidlyrejected unless a high degree of immunosuppression is present.The rules that govern graft acceptance and rejection, and the immu-nological basis of successful graft acceptance, are well defined(Figure 11.1).

Introductory Immunology. DOI: http://dx.doi.org/10.1016/B978-0-12-420030-2.00011-1Copyright © 2014 Elsevier Inc. All rights reserved.

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TISSUE HISTOCOMPATIBILITY

The basic architecture of tissues between individuals is quite similar.Indeed, a kidney is a kidney; the liver functions in a similar manner fromone person to another. Unfortunately, significant differences in moleculespresent on the surface of cells exist between genetically different indivi-duals. These discrepancies must be taken into consideration during trans-fer of blood, cells, and tissue. Specifically, serum must be matched to limitinteractions with naturally occurring reactive antibodies, blood cells mustbe matched for carbohydrate markers on their surface, and solid tissuesmust be matched for overall genetic histocompatibility.

Natural IsohemagglutininsA subpopulation of IgM isotype antibodies includes the naturalisohemagglutinins, which are reactive with the red blood cell moleculesof the ABO series. The ABO blood group epitopes are carbohydrates innature; antibodies elicited by environmental (bacterial) carbohydratemotifs cross-react with human A or B blood group antigens on redblood cells. It is therefore critical to match the ABO blood types when

Donor Recipient

Accept

Accept

Reject

Reject

Autograft

Allograft

Heterograft(xenograft)

Isograft(syngraft)

From self to self(MHC identical)

Persons of genetic identity(MHC matched)

From non-self(MHC mismatch)

Different species(complete MHC mismatch)

Figure 11.1 Transplantation acceptance as function of recipient and donor genetic similarity. Tissue transplanta-tion is governed by immunological rules that allow graft acceptance according to degree of genetic relatednessbetween recipient and donor.

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giving whole blood or serum. Table 11.1 gives the reactivity ofisohemagglutinin antibodies normally found in patients with the vari-ous blood groups.

In addition to the ABO antigenic category, an antigen called theRh factor (rhesus factor) is also present on blood cells. The Rh factorsmust be matched; Rh negative blood is only given to Rh negativepatients. A Rh negative individual will make antibodies to the Rh fac-tor if Rh positive blood is given. If antibodies are present to the Rhfactor, they will cause agglutination of the donated blood cell. Rh posi-tive blood or Rh negative blood may be given to Rh positive patients,as those individuals do not make antibodies to molecules they alreadypossess on their own cells.

Human Leukocyte AntigensThe major histocompatibility complex (MHC) antigens are the stron-gest indicator for inducing allograft rejections. These are the humanleukocyte antigens (HLA) discussed previously that allow T cells to rec-ognize presented antigen as a first step in activation events. Relative toimmune function, the class I HLA molecules (HLA-A, HLA-B, HLA-C)are found on all nucleated cells and mediate recognition of endogenousantigen by CD81 cytotoxic T cells. The class II HLA molecules(HLA-DR, HLA-DP, HLA-DR) are on the surface of professionalantigen-presenting cells (APCs), and show exogenous antigen toCD41 T helper subsets. Subsets of these molecules are inherited fromboth parents, allowing unique patterns to be expressed in their off-spring. The nature of these molecules includes a high degree of poly-morphism, which essentially creates high differences betweenindividuals. As a group, these sets of HLA surface molecules arereferred to as alloantigens. During transplantation, the histocompatibil-ity alloantigens expressed on donor tissue are recognized by bothCD41 T helper and CD81 cytotoxic lymphocytes present in the

Table 11.1 Natural IsohemagglutininsBlood Type Antigen Present on RBCs Isohemagglutinin Reactivity

A A Anti-B

B B Anti-A

AB A and B None

O None Anti-A and Anti-B

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recipient host. The greater disparity between the host and the donor,the greater the lymphocytic reactivity and chance for subsequent tissuerejection. Minor histocompatibility antigens, as well as tissue specificdifferences between the host and the donor, may also contribute tograft rejection.

Tissues transplanted to immunoprivileged sites do not typicallyrequire MHC matching. For example, corneal transplants do not rou-tinely require HLA matching. The fetus is another example of “toler-ated” nonmatched tissue. Although there are common antigensbetween mother and child, there are also numerous paternal-derivedmoieties. Factors that allow tolerance include downregulation of MHCon the developing fetus and change in environmental cytokines or fac-tors produced by both the mother and the fetus.

ALLOGRAFT REJECTION

Allograft rejection involves a series of humoral and cellular responses(Figure 11.2). The immune response involved in allograft rejectionspans a wide variety of defined mechanisms. Preformed antibodies canbind to donor tissue, establishing a nidus for direct killing via comple-ment deposition. Antibodies can also function in concert with naturalkiller cells in an antibody-dependent cell cytotoxic manner to lyse non-matched target tissue. CD41 cells recognize class II MHC moleculeson the donor tissue (HLA-DP, HLA-DQ, HLA-DR), and are inducedto secrete IL-2, IFN-γ, and TNF-α. These in turn activate CD81cells, natural killer cells, and incoming macrophages. The Th1 CD41cells also give signals to activate the Th2 CD41 group to secrete cyto-kines IL-4, IL-5, and IL-10, which can induce B cells to undergo acti-vation and immunoglobulin production, as well as isotype classswitching.

The mechanisms involved permit the establishment of rejection cat-egories. These include characterization of rejection as being hyper-acute, accelerated, acute, and chronic.

Hyperacute RejectionHyperacute rejection occurs within minutes of transplantation in indi-viduals who are MHC mismatched, or in individuals preexposed to thedonor’s MHC types by prior grafting or blood transfusion. The end

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result is graft tissue loss in a nonreversible manner. The basis relates topreexisting antibodies reactive with the mismatch. Natural IgM antibo-dies are present to cross-reactive epitopes on pathogens which mimicthe carbohydrates within components on nonmatched blood cells.These antibodies immediately recognize the foreign tissue and activatecomplement, which in turn releases factors attracting and activatingneutrophils.

Accelerated RejectionAccelerated rejection, also called “second set” rejection, is relativelyrare but occurs with multiple transplants from genetically relateddonors. Recipients that have rejected a previous allograft tend to rejecta second allograft from the same donor significantly faster.

RBC

RBC

RBCRBC

RBC ABOantigens

Host tissue

Donor tissue

HyperacuterejectionPreformedantibodies to bloodantigens orMHC antigens(minutes to hours)

Acute rejectionT-cell response directed todonor MHC or tissue antigens(10–30 days)

Chronic rejectionT-cell and B-cellresponse to donorminor MHC antigens(months to years)

Graft-versus-host responseDonor T/B-cellattack on host MHCantigens

RBC DonorT-cellCD8+

DonorT-cellCD4+

APC

Class IIMHC

Class IMHC

APC

CTL

B

TH

CTL

IL-4

IFN-γ

Class IIMHC

β2M

β2M

Figure 11.2 Allograft rejection. Immune-mediated tissue rejection is characterized by the response speed towarddonor tissue, which is directly related to immune mechanisms involved in the rejection process.

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Acute RejectionAcute rejection, also called “first set” rejection, occurs between 10 and30 days’ post-grafting in untreated recipients. This is the expected timefor reactive T-cell populations to expand and react. Both T helper andT cytotoxic cells are usually required, although the direct cytotoxicevent is delivered by CD81 CTLs. Reactions usually occur later inimmunosuppressed recipients, depending on level of immunosuppres-sion success.

Chronic RejectionChronic rejection occurs over months to years post-transplant. It is acomplex reaction involving maturation of both T and B lymphocyteresponses. Antibodies are directed at the foreign (non-self) antigenswithin the graft. Subsequent deposition of antibody�antigen com-plexes leads to targeted destruction of graft tissue and indirect damageto vascular beds. Chronic rejection leads to permanent damage that isdifficult (if impossible) to reverse with immumosuppressants.

The molecular mediators involved in graft rejection are depicted inFigure 11.3. It is relatively straightforward to envision the acute andchronic mechanisms discussed as being a direct recognition by the hostT cell to a combination of foreign MHC and foreign antigens.However, keep in mind that it is also possible for alloantigens to bepresented by host APCs. When host cells pick up pieces of the donortissue and present donor-derived peptides, they can also be targeted fordestruction. Indirect recognition of host lymphocytes may thereforecontribute to destruction of self-tissue that is physically near thegrafted organ.

GRAFT-VERSUS-HOST DISEASE

GVHD occurs when immunocompetent lymphocytes from the donortissue are inadvertently delivered to the host during the transplantationprocess. The recipient host, who is immunosuppressed at the time oftransplantation, does not reject the alloreactive cells. Over time, theseinfiltrating donor cells expand, culminating in a pool of donor cellsreactive to host tissue. GVHD can occur when there is a mismatch ofHLA (class I or class II), or if there are a significant number of differ-ences in minor histocompatibility antigens, such as that seen in closelymatched siblings. A common GVHD occurrence is post-bone marrow

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transplantation, where alloreactive hematopoetic stem cells are deliv-ered as a form of gene therapy. These pluripotent stem cells give riseto all phenotypes of white blood cells; however, the pool of trans-planted cells often contains mature lymphocytes that are capable ofrecognizing differences in HLA between the donor and host.Stringency of T-cell depletion prior to transplantation reduces thisoccurrence.

PRE-TRANSPLANTATION HISTOCOMPATIBILITY EVALUATION

Multiple laboratory methods are used to evaluate tissue histocompati-bility between donor and recipient. Methods allow matching of tissuesbetween individuals, with a higher degree of graft survival directly

Allograftcell T-cell

IL-2, IL-12

T Helper

NK cell

ADCC Macrophage

Cytolysis

Complement

Plasmacell

Antibodies

Antibody-mediated lysis

C′ C′C′

Lytic enzymes

TCR TCR

CD3

CD4

CD8

CD3

IL-2, IFN-γ

B cell

CTL

IL-2, IL-4IL-5, IL-6

Figure 11.3 Allograft rejection is mediated by cellular and molecular mediators. The specific molecular mediatorsof allograft graft rejection are a function of the responding immune cell phenotypes involved in tissue recognition.

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related to level of similarity. Any donor-recipient HLA incompatibilitycan result in an immune response, rejection, and possible graft loss.And while immunosuppressants may obviate the impact of HLAmatching for both short- and long-term graft outcome, it is preferredto limit mismatch prior to transplantation.

Any potential donor must undergo extensive screening prior totransplantation. This begins with a test for host antibody reactivity todonor target cells. In essence, this simple test can identify reactiveanti-donor antibodies by examining the level of cytotoxicity andlymphocytotoxicity of these antibodies to lyse cells in the presence ofcomplement components. The purpose of the cross-match is to detectclinically relevant IgG anti-donor antibodies to prevent hyperacute,accelerated, or chronic rejection. The next level of tests examinescellular reactivity, accomplished using host and donor T cells in amixed lymphocyte reaction to assess direct reactivity to allogeneicMHC between individuals. Basically, if T cells are reactive to alloge-neic molecules, they will undergo rapid replication and produce diag-nostic secretion of cytokine subsets.

Recent technological advances now permit identification of haplo-type distinctions between individuals without cell culture methods.These methods are especially useful when comparing relationships ofparents and siblings to the recipient. One particular method, calledHLA-DNA (also called PCR typing), uses polymerase chain reaction(PCR) and sequence-specific oligonucleotide probes to rapidly identifyDNA-genomic subtypes. DNA primers can be used which are specificfor individual or similar groups of HLA alleles, allowing amplificationof relevant genomic DNA. This type of screening is especially usefulwhen donor tissue is of cadaveric (deceased) origin.

IMMUNOSUPPRESSIVE DRUGS TO PREVENT ALLOGRAFTREJECTION

At the present time, there is no successful clinical protocol to inducecomplete tolerance to allografts. All patients require daily, lifelongtreatment with immunosuppressive agents to inhibit graft rejection.All immunosuppressive agents used in clinical practice have draw-backs relating to toxicity and side effects, or to failure to providesufficient levels of downregulated lymphocytic response. On one hand,

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inadequate immunosuppression allows the recipient to mount animmune response, causing allograft rejection. On the other hand,excessive immunosuppression can lead to development of opportunisticinfections and neoplasia.

Immunosuppressive TherapyImmunosuppressive agents are often used to control reactions prior tograft rejection. These agents fall into categories dependent on targetedfunction and immune modification desired (Table 11.2). Prior to trans-plantation, agents are given to the recipient at a relatively high level toquiet immune reactivity, allowing for greater success and acceptance oftissue immediately post-transplantation. After the tissue has beenplaced within the host, the major concern revolves around targetingthe immune system in a manner which prevents reactivity.Maintenance therapy is usually given at a low level to keep theimmune system operational but quiet, without completely shuttingdown reactivity to opportunistic infections. It is only when clinicalsymptoms arise indicating initiation of active rejection that specificand aggressive immune suppressants are used. In this case, targetedtherapeutics are administered to support mechanisms which disruptimmune events and even kill rapidly expanding lymphocytes that dem-onstrate reactivity to the donor organ.

Table 11.2 Immunosuppressant Drugs and TherapeuticsClass Mechanism of Action Example

Corticosteroids Blocks multiple cytokineexpression

• Prednisone• Prednisolone• Methylprednisolone

Cytotoxic agents Blocks DNA synthesis or replicationin proliferating cells; can suppressAPC processing

• Azathioprine (AZA)• Cyclophosphamide• Hydroxychloroquine

Immunophilin ligand Blocks T-cell activation andgene transcription

• Cyclosporine (CsA)• Tacrolimus (FK506)

Proliferation signal inhibitors Blocks intracellular kinases • Sirolimus (SRL)• Mycophenolate mofetil (MM)

Immunosuppressive antibodies Specific targeting of adaptivecellular functions

• Anti-lymphocyte globulin• Anti-thymocyte globulin• Anti-CD3 MAb (OKT3)• Rh(D) immune globulin• Etanercept (anti-TNFα/β)• Daclizumab (anti-IL2R)

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Immunosuppressive therapy has had a significant impact on boththe prevention and treatment of rejection. Yet, suppressing the immuneresponse has consequences, such as increased risk of infections and cer-tain types of malignancies. While steroids remain an important immu-nosuppressive clinical tool, recent advances in protocol developmentlimit their use to minimize known side effects. Other therapeutics suchas Tacrolimolus are effective; however, a major concern remains sur-rounding nephrotoxicity. Targeted agents, including polyclonal andmonoclonal antibodies, are becoming increasingly useful in the arsenalagainst rejection of transplanted tissue. However, they often leave therecipient highly susceptible to infection, which remains a major causeof mortality post-transplantation.

SUMMARY

• The immunological rules for transplant acceptance or rejection aregoverned by recipient responses to histocompatibility molecules ondonor cells.

• Allograft reactivity, and the speed of rejection, is governed by cellphenotypes and molecules involved in reactivity to donor histocom-patibility antigens.

• GVHD represents a state where immune competent cells from thedonor tissue escape initial destruction and lead to subsequent reac-tivity against recipient tissues.

• Modern laboratory techniques can use genetic sequences to identifypotential histocompatibility mismatches. Therapeutics have evolvedto specifically target immune responses detrimental to graftacceptance.

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