Immuno 19

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.alloantigens-

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antigen which varies between members of the same species

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.alloreactions

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.immune responses directed against alloantigens

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.immunogenetics

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.a subfield of immunology devoted to the genetics of alloantigens

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autograft

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graft of tissue from one site to another site on the same individual (no rejection results)

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syngeneic graft or isograft

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graft of tissue from one individual to another individual that is genetically identical (no rejection results)

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allograft or allogeneic transplant

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graft of tissue from one person to another person that is genetically different (rejection of tissue can result)

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transplant rejection:

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alloreactions developed by a recipient’s immune system that are specific for grafted tissue (tissue is killed);

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graft vs. host (GVH) reaction:

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reaction mounted by mature T cells contained in grafted tissue against tissues of the recipient

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• transplantation of tissues to replace damaged or worn-out organs required solutions to three basic problems:

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1) transplant must be introduced into the recipient in a way that allows it to perform its basic function (relatively routine “plumbing”)
2) health of the donor and recipient must be maintained during the transplant surgery (relatively routine as well)
3) the immune system of the recipient must be prevented from mounting adaptive immune responses that destroy the grafted tissue (may never be considered routine)
•• while techniques for performing many transplant surgeries have progressed to the point that the 1st two problems are usually solved, to date there is no known procedure for selectively suppressing responsiveness to grafted tissues…systemic suppression of immune responses must be elicited for a recipient to tolerate an allogeneic graft

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• immune responses mounted by a recipient that are directed at transplanted tissues are caused by genetic differences between the donor and the recipient (polymorphic gene expression; e.g. MHC molecules)

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•• the most important of the genetic differences are the differential expression of HLA molecules (MHC class I molecules)
••• the HLA genes are highly polymorphic (meaning that there are many different alleles for each of the MHC class I molecules that can be expressed within the population); the differences in HLA molecules are the basis of most of the alloreactivity produced by a recipient’s immune system

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A. BLOOD TRANSFUSIONS-

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transfer of blood from one individual to another is a type of tissue transplantation

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• blood transfusion is the easiest and most commonly used transplantation procedure
• the barriers to transplanting blood are fewer than for any other tissue in the body
•• transfused blood components are usually only needed for a short time until the recipient’s bone marrow can resupply the blood components lost during surgery or trauma
•• since RBCs do not express MHC class I or MHC class II molecules, the alloantigens that cause most transplant rejections are not a problem

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• life-threatening alloreactions can result from blood transfusions, however. These alloreactions are based on the structural polymorphisms in the carbohydrates on glycolipids of the erythrocyte surface. These primary differences are known as the A, B, O system of blood group antigens

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•• because the blood group antigens are structurally very similar to surface carbohydrate molecules found on the surface of many bacteria, most people have produced antibodies (in response to bacterial infection) that react with the blood group antigens that are different from those that they themselves express
••• for instance, a person that expresses the O blood group antigen on his/her RBCs will have antibodies that bind to both the A and B blood group antigens
••• remember, each person should be immunologically tolerant of their own blood group antigen (review negative selection of B cells and T cells)

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donors and recipients for blood transfusions must be matched for the A, B, O system of blood group antigens

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• if a person that has type O blood receives a transfusion of type A or type B blood, that person’s anti-A or anti-B antibodies will bind to the transfused RBCs

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•• this results in complement activation and rapid clearance of the transfused RBCs
••• thwarts the purpose of the transfusion
••• results in fever, chills, shock, renal failure, and sometimes death (symptoms similar to those experiences during a type II hypersensitivity reaction)

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• Rh factors: there are 50 defined Rh blood group antigens that are polymorphic with respect to expression within the population. The most important of these factors with respect to blood transfusion compatablity is the RhD factor; thus, the commonly used termed “Rh factor” refers to the RhD antigen.
•• unlike the ABO antigens, there are no structures on normal flora bacteria that are similar to RhD. Therefore, people that do not express RhD will not have antibodies specific for RhD in their circulation. However, if an RhD-negative individual receives a transfusion of RhD-positive blood, they will produce an RhD-specific antibody response. Upon any subsequent transfusion with RhD-positive blood, that person would experience a life-threatening blood reaction. Therefore, RhD expression should be considered prior to transfusion

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Pregnancy is an interesting situation: the fetus is essentially an allograft (due to differences in MHC haplotype from the mother) that can be tolerated repeatedly (IS3-Figure 15.4). The mysterious lack of rejection of the fetus has puzzled generations of reproductive immunologists, and the reason(s) for this lack of response remains unclear
•• the placenta may serve as a partial barrier to the mother’s T cells; the placenta is fetal tissue, and it lacks expression of MHC class I molecules
•• another factor could be the array of cytokines that are expressed by the trophoblast (placenta) and the uterine epithelium; these cells produce TH2-type cytokines, which tend to promote antibody responses while suppressing T cell mediated responsiveness

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Pregnancy is an interesting situation: the fetus is essentially an allograft (due to differences in MHC haplotype from the mother) that can be tolerated repeatedly (IS3-Figure 15.4). The mysterious lack of rejection of the fetus has puzzled generations of reproductive immunologists, and the reason(s) for this lack of response remains unclear
•• the placenta may serve as a partial barrier to the mother’s T cells; the placenta is fetal tissue, and it lacks expression of MHC class I molecules
•• another factor could be the array of cytokines that are expressed by the trophoblast (placenta) and the uterine epithelium; these cells produce TH2-type cytokines, which tend to promote antibody responses while suppressing T cell mediated responsiveness

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• this problem can be treated via passive immunization with a product known as RhoGam; RhoGam is a preparation of antibodies that are specific for RhD+ erythrocytes. Immediately following the first parturition (birth of the 1st fetus), the mother can be treated with RhoGam or Rho(D) immune globulin (IgG specific for Rh factor D) to destroy all of the fetal RBCs that enter the mother’s circulation. This treatment prevents the mother from producing an Rh-specific immune response by eliminating the antigen before the immune response can be initiated. Therefore, she should have no problems carrying a second Rh+ pregnancy.

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• because it is possible that a pregnant mother can have a minor accident that causes fetal blood to enter her circulation, RhoGam treatment can be given during pregnancy. It is my understanding that RhoGam treatment is typically initiated during the 6th month of pregnancy for most Rh-neg mothers carrying an Rh-positive fetus.

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B. TISSUE AND ORGAN TRANSPLANTATION-transplant of any tissue other than RBCs (nucleated cells)
1. hyperacute transplant rejection

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• A, B, O antigens are also expressed on the endothelial cells of blood vessels, and as such are an important determinant to consider upon organ/tissue transplantation
•• therefore, if a person with type O blood receives an organ transplant from a donor with blood type A, the anti-A antibodies of the recipient would bind to the A antigens along the vascular endothelium of the grafted tissue
••• complement activation would then occur throughout the vasculature of the graft, and very rapid graft rejection would occur (12-48 hrs)

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• preformed antibodies specific for allogeneic HLA antigens can also mediate hyperacute graft rejection

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•• anti-HLA antibodies can be generated in a recipient (prior to transplant, of course) as a result of immune responses to a previous pregnancy, blood transfusion, or a previous tissue graft
•• the degree to which a patient seeking a transplant has been sensitized to potential donors is assessed by testing their sera against a panel of individuals from the population; the results are expressed as the percentage of positive reactions against the panel: panel-reactive antibody or PRA

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2. acute graft rejection
• acute rejection is mediated by effector T cells that respond to HLA differences between the donor and the recipient

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•• acute rejection is the result of a newly formed acquired immune response that is initiated against alloantigens following the graft procedure (no preformed responses to the alloantigens, because there has been no previous exposure)

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• much of what is known about acute rejection has been learned thru studies of skin grafts between different strains of mice (see JW7-Figure 14.39)
• when a skin graft is transplanted from one mouse to another mouse of the same inbred strain (identical MHC expression), the grafted tissue is tolerated
• when a skin graft is transplanted from one mouse to another mouse of a different inbred strain (different MHC expression), the graft is always rejected (see RBM-Figure 23.19)
•• rejection usually occurs between days 11-15 post transplantation, reflecting the time necessary for an acquired immune response to form against the grafted tissue and for the tissue to be killed
• if a mouse that has previously received an allogeneic transplant (and rejected the tissue), receives a second transplant from the same allogeneic donor, the new graft is rejected much faster (6-8 days post transplant)
•• this more rapid rejection is a reflection of the preformed acquired immune response that was produced against the first graft

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• there are two pathways by which HLA molecules can stimulate acquired immune responses

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1. direct pathway: naïve T cells of the recipient recognize self peptides of the donor loaded onto donor HLA molecules on donor APCs (see IS3-Figure 15.11)
2. indirect pathway: peptides derived from donor HLA molecules are processed and presented by recipient APCs to naïve T cells of the recipient; the source of these donor HLA molecules is primarily donor APCs which migrate to secondary lymphoid tissue of the recipient and undergo apoptotic death. Components of these dead cells are phagocytosed/endocytosed by resident APCs, and the antigens are processed primarily via the MHC class II processing and presentation pathway; the primary effectors generated via the indirect pathway are CD4 effector cells; the CD4 T cell effectors generated via the indirect pathway can participate in acute graft rejection, but they are a critical component of chronic rejection due to their role in the alloantigen-specific antibody response that mediates chronic rejection

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3. minor histocompatability antigen-mediated rejection

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• results from immune responses to minor histocompatability antigens (when donor and recipient are identically matched with respect to MHC expression)
•• while the MHC genes are the most polymorphic genes in humans, there are other polymorphic genes that can have an impact on transplant outcome (minor histocompatability antigens) (see IS3-Figure 15.31)
•• rejection of tissue that is mediated solely by immune responses directed towards minor histocompatability antigens usually takes about 60 days

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4. chronic rejection
• can occur months or years after transplantation
• typically correlates with the presence of antibodies specific for MHC class I molecules of the grafted tissue

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• is characterized by reactions in the vasculature of the graft that result in thickening of the vessel walls, and a narrowing of their lumina. Gradually, the blood supply to the tissue is reduced to the point that the function of the grafted tissue is lost (see IS3-Figure 15.10)
•• chronic rejection appears to be mediated by alloreactive, MHC class I-specific antibodies that bind to vascular epithelia of the grafted tissue, attracting Fc receptor bearing cells (monocyte/macrophages and neutrophils); the chronic inflammation caused by these cells eventually results in tissue damage and death of the grafted tissue
•• the reactions responsible for this type of tissue rejection are poorly understood
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• chronic rejection is responsible for the failure of more than 50% of all kidney and heart transplants within 10 years of transplant procedure

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C. HLA MATCHING AND IMMUNE SUPPRESSION IMPROVE TRANSPLANTATION OUTCOME

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• the more closely related (with respect to HLA expression) the donor and recipient tissues are, the better the outcome of the transplant (see IS3-Figure 15.13)
•• grafts between identical twins are routinely accepted (identical MHC expression)
•• grafts between members of the same family are likely to be successful (because finding a good HLA match is more likely than in the general population)

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• unfortunately, due to the polygeny and extreme polymorphism of MHC expression in the population at large, it is difficult to match donor tissue to a recipient with the exact same complement of HLA antigens

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•• immunosuppressive drugs can be used to suppress the recipient’s immune reactivity to allogeneic tissue grafts
••• corticosteroids: prevents cell activation
••• cytotoxic drugs: kill proliferating cells; cyclosporin A, tacrolimas, and rapamycin selectively inhibit T cell activation
** unfortunately, suppression of the immune system to allow tolerance to grafted tissue prevents the immune system from reacting normally to pathogens that the host encounters

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• HLA matching is not necessary for some tissues

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•• corneal transplants do not require HLA-matching because the cornea is not vascularized (immunologically privileged tissue) and is therefore unavailable to immune effectors
•• liver transplantation does not require HLA cross-matching (in fact, some claim that outcome of liver transplantation is inversely correlated with degree of HLA-match); ABO type is the only genetic factor considered prior to liver transplantation
••• the liver has a specialized architecture and vasculature, and hepatocytes express very low levels of HLA class I or HLA class II
••• use of cyclosporine A and tacrolimus does markedly improve outcome of liver transplantation

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D. GRAFT VS. HOST DISEASE
• the major cause of morbidity and mortality following bone marrow transplantation is acute graft vs. host disease
•• unlike solid organ transplants, where alloreactions are limited to the transplanted organ, alloreactions following bone marrow transplantation are systemic

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• the primary targets for GVHD are the skin, intestines, and liver (see IS3-Figure 15.27)
• GVHD is mediated by mature T cells in the donor tissue that reacts to antigens of the recipient’s tissues (see IS3-Figure 15.26)
• to prevent GVH disease, mature T cells can be depleted from the bone marrow prior to grafting
• drug treatment can also help to control the incidence and severity of GVH disease (methotrexate in combination with cyclosporin)