Transplantation Immunology Chapter 17

Transplantation is a widely used treatment for replacement of nonfunctioning organs and tissues with healthy organs or tissues Technically, transplantation is the process of taking cells, tissues, or organs, called a graft, from one individual and placing them into a (usually) different individual Donor, Recipient, Transfusion refers to the transfer of circulating blood cells or plasma from one individual to another

Transplantation of cells or tissues from one individual to a genetically nonidentical individual invariably leads to rejection of the transplant due to an adaptive immune response

A graft transplanted from one individual to the same individual is called an autologous graft. A graft transplanted between two genetically identical or syngeneic individuals is called a syngeneic graft. A graft transplanted between two genetically different individuals of the same species is called an allogeneic graft (or allograft). A graft transplanted between individuals of different species is called a xenogeneic graft (or xenograft). The molecules that are recognized as foreign on allografts are called alloantigens, and those on xenografts are called xenoantigens. The lymphocytes and antibodies that react with alloantigens or xenoantigens are described as being alloreactive or xenoreactive, respectively.

The molecules responsible for almost all strong (rapid) rejection reactions are called major histocompatibility complex (MHC) molecules Allogeneic MHC molecules of a graft may be presented for recognition by the T cells of the recipient in two fundamentally different ways, called direct and indirect Initial studies showed that the T cells of a graft recipient recognize intact, unprocessed MHC molecules in the graft, and this is called direct presentation of alloantigens Subsequent studies showed that sometimes, the recipient T cells recognize graft MHC molecules only in the context of the recipient’s MHC molecules, implying that the recipient’s MHC molecules must be presenting allogenic graft MHC proteins to recipient T cells. This process is called indirect presentation,

Direct Presentation of MHC Alloantigens

Indirect Presentation of Alloantigens

In the setting of any transplant between genetically nonidentical donor and recipient, there will be polymorphic antigens other than MHC molecules against which the recipient may mount an immune response. These antigens typically induce weak or slower (more gradual) rejection reactions than do MHC molecules and are therefore called minor histocompatibility antigens. Most minor histocompatibility antigens are proteins that are processed and presented to host T cells in association with self MHC molecules on host APCs (i.e., by the indirect pathway)

Activation of Alloreactive Lymphocytes

The Mixed Lymphocyte Reaction The response of alloreactive T cells to foreign MHC molecules can be analyzed in an in vitro reaction called the mixed lymphocyte reaction (MLR) The MLR is used as a predictive test of T cell–mediated graft rejection. Studies of the MLR were among the first to establish the role of class I and class II MHC molecules in activating distinct populations of T cells (CD8+ and CD4+, respectively)

The Mixed Lymphocyte Reaction

PATTERNS AND MECHANISMS OF ALLOGRAFT REJECTION

Hyperacute Rejection Hyperacute rejection is characterized by thrombotic occlusion of the graft vasculature that begins within minutes to hours after host blood vessels are anastomosed to graft vessels and is mediated by preexisting antibodies in the host circulation that bind to donor endothelial antigens In the early days of transplantation, hyperacute rejection was often mediated by preexisting IgM alloantibodies, which are present at high titer before transplantation. Such “natural antibodies” are believed to arise in response to carbohydrate antigens expressed by bacteria that normally colonize the intestine. The best known examples of such alloantibodies are those directed against the ABO blood group antigens expressed on red blood cells One possible mechanism of this resistance to hyperacute rejection is increased expression of complement regulatory proteins on graft endothelial cells, a beneficial adaptation of the tissue that has been called accommodation

Hyperacute Rejection

Acute Rejection Acute rejection is a process of injury to the graft parenchyma and blood vessels mediated by alloreactive T cells and antibodies In Acute Cellular Rejection, the principal mechanism of acute cellular rejection is CTL- mediated killing of cells in the graft. On histologic examination, this type of rejection is characterized by infiltrates of lymphocytes, which invade and destroy graft components. There are many lines of evidence that support the role of CTLs in acute cellular rejection In Acute Antibody-Mediated Rejection, Alloantibodies cause acute rejection by binding to alloantigens, mainly HLA molecules, on vascular endothelial cells, causing endothelial injury and intravascular thrombosis that results in graft destruction

Acute Rejection

Chronic Rejection and Graft Vasculopathy As therapy for acute rejection has improved, the major cause of the failure of vascularized organ allografts has become chronic rejection A dominant lesion of chronic rejection in vascularized grafts is arterial occlusion as a result of the proliferation of intimal smooth muscle cells, and the grafts eventually fail mainly because of the resulting ischemic damage

PREVENTION AND TREATMENT OF ALLOGRAFT REJECTION

Methods to Reduce the Immunogenicity of Allografts To avoid hyperacute rejection, the ABO blood group antigens of the graft donor are selected to be identical to those of the recipient In kidney transplantation, the larger the number of MHC alleles that are matched between the donor and recipient, the better the graft survival Patients in need of allografts are also tested for the presence of preformed antibodies against donor MHC molecules or other cell surface antigens. Two types of tests are done to detect these antibodies. In the panel reactive antibody test, patients waiting for organ transplants are screened for the presence of preformed antibodies reactive with allogeneic HLA molecules prevalent in the population

Methods to Reduce the Immunogenicity of Allografts If a potential donor is identified, the cross matching test will determine whether the patient has antibodies that react specifically with that donor’s cells. The test is performed by mixing the recipient’s serum with the donor’s blood lymphocytes. Complement-mediated cytotoxicity tests or flow cytometric assays can then be used to determine if antibodies in the recipient serum have bound to the donor cells

Methods to Induce Donor-Specific Tolerance Costimulatory blockade Hematopoietic chimerism: transfusion of donor blood cells into the graft recipient inhibits rejection Transfer or induction of regulatory T cells Administration of soluble MHC proteins or peptides under conditions predicted to induce tolerance

XENOGENEIC TRANSPLANTATION A major immunologic barrier to xenogeneic transplantation is the presence of natural antibodies that cause hyperacute rejection Even when hyperacute rejection is prevented, xenografts are often damaged by a form of acute vascular rejection that occurs within 2 to 3 days of transplantation Xenografts can also be rejected by T cell–mediated immune responses to xenoantigens

BLOOD TRANSFUSION AND THE ABO AND Rh BLOOD GROUP ANTIGENS If such individuals are given blood cells expressing the target antigen, the preexisting antibodies bind to the transfused cells, activate complement, and cause transfusion reactions, which can be life threatening

ABO Blood Group Antigens

Lewis Antigen The same glycoproteins that carry the ABO determinants can be modified by other glycosyl transferases to generate minor blood group antigens Lewis antigens have recently received much attention from immunologists because these carbohydrate groups serve as ligands for E-selectin and P-selectin

Rhesus (Rh) Antigen Rh antigens are nonglycosylated, hydrophobic cell surface proteins found in red blood cell membranes and are structurally related to other red cell membrane glycoproteins with transporter functions Rh proteins are encoded by two tightly linked and highly homologous genes, but only one of them, called RhD, is commonly considered in clinical blood typing The major clinical significance of anti-Rh antibodies is related to hemolytic reactions associated with pregnancy that are similar to transfusion reactions Subsequent pregnancies in which the fetus is Rh positive are at risk because the maternal anti-Rh antibodies can cross the placenta and mediate the destruction of the fetal red blood cells. This causes erythroblastosis fetalis (hemolytic disease of the newborn) and can be lethal for the fetus

HEMATOPOIETIC STEM CELL TRANSPLANTATION Examples of such diseases that can be cured by hematopoietic stem cell transfer are adenosine deaminase (ADA) deficiency, X-linked severe combined immunodeficiency disease, and hemoglobin mutations such as beta-thalassemia major and sickle cell disease Allogeneic hematopoietic stem cells are rejected by even a minimally immunocompetent host, and therefore the donor and recipient must be carefully matched at all MHC loci The mechanisms of rejection of bone marrow cells are not completely known, but in addition to adaptive immune mechanisms, hematopoietic stem cells may be rejected by NK cells

Graft-Versus-Host Disease (GVHD) GVHD is caused by the reaction of grafted mature T cells in the marrow inoculum with alloantigens of the host Acute GVHD is characterized by epithelial cell death in the skin, liver (mainly the biliary epithelium), and gastrointestinal tract. It is manifested clinically by rash, jaundice, diarrhea, and gastrointestinal hemorrhage. When the epithelial cell death is extensive, the skin or lining of the gut may slough off. In this circumstance, acute GVHD may be fatal Chronic GVHD is characterized by fibrosis and atrophy of one or more of the same organs, without evidence of acute cell death. Chronic GVHD may also involve the lungs and produce obliteration of small airways. When it is severe, chronic GVHD leads to complete dysfunction of the affected organ.

Immunodeficiency After Bone Marrow Transplantation Radiation therapy and chemotherapy used to prepare recipients for transplantation are likely to deplete the patient’s memory cells and long-lived plasma cells, Recipients are susceptible to viral infections, especially cytomegalovirus infection, and to many bacterial and fungal infections They are also susceptible to Epstein-Barr virus–provoked B cell lymphomas Recipients commonly receive prophylactic antibiotics and anti-cytomegalovirus therapy and are often actively immunized against capsular bacteria such as pneumococcus before transplantation

There is great interest in the use of pluripotent stem cells to repair tissues with little natural regenerative capacity, such as cardiac muscle, brain, or spinal cord One approach is to use embryonic stem cells, which are pluripotent stem cells derived from the blastocyst stage of human embryos