Transplantation

What are some clinical laboratory tests routinely performed to reduce the risk for immunologic rejection of allografts?

-ABO blood typing -Tissue typing -Detection of preformed antibodies in the recipient that recognize HLA and other antigens representative of the donor population -Detection of preformed antibodies in the recipient that bind to antigens of an identified donor's leukocytes (crossmatching)

What two tests can be performed to detect preformed antibodies against donor MHC molecules?

-Panel reactive antibody test -Crossmatching test

The frequency of T cells in a normal individual that recognize a single allogeneic MHC molecule is as high as ______ of all T cells.

1% to 2%

1% to 2% recognition of allogeneic MHC molecules is _______ times greater than the frequency of T cells specific for any microbial peptide displayed by self MHC molecules.

100 to 1000

Since 1990, the 1-year survival rate of kidney allografts has been better than 90%, but the 10-year survival rate has remained about _____ despite advances in immunosuppresive therapy.

60%

What is cyclosporine?

A fungal peptide that binds with high affinity to a ubiquitous cellular protein called cyclophilin

What is a widely used antibody for rejection?

A mouse monoclonal antibody called OKT3 that is specific for human CD3

What is acute rejection?

A process of injury to the graft parenchyma and blood vessels mediated by alloreactive T cells and antibodies

What is a graft transplanted between two genetically different individuals of the same species called?

Allogeneic graft (allograft)

Why is the onset of acute rejection delayed?

Alloreactive effector T cells and antibodies take time to be generated from naive or resting memory T cells in response to the graft

What is direct presentation of alloantigens?

An intact MHC molecule is displayed by donor APCs in the graft and recognized by recipient T cells without a need for host APCs

What is the role of antibodies in treating graft rejection?

Antibodies that react with T cell surface structures and deplete or inhibit T cells can be used to treat acute rejection episodes

What is a graft transplanted from one individual to the same individual called?

Autologous graft

What was the first antimetabolite to be developed for the prevention and treatment of rejection?

Azathioprine

What is the role of the cyclosporine-cyclophilin complex?

Binds to and inhibits the ezymatic activity of the calcium/ calmodulin-activated serine/ threonine phosphatase calcineurin, resulting in *inhibition of IL-2 production*

How are most high-affinity alloantibodies produced?

By helper T cell-dependent activation of alloreactive B cells

Monoclonal antibodies are now in clinical use that are specific for _______, the alpha subunit of the IL-2 receptor.

CD25

Direct allorecognition can generate both ________ that recognize graft antigens and contribute to rejection.

CD4+ and CD8+ T cells

How do alloreactive CD8+ T cells cause graft rejection?

CD8+ T cells differentiate into cytotoxic T lymphocytes, which kill nucleated cells in the graft that express the allogeneic class I MHC molecules. CTLs also secrete inflammatory cytokines, which can contribute to graft damage

What are the two patterns of acute rejection?

Cellular and humoral

What is now the major cause of the failure of vascularized organ allografts?

Chronic rejection

What reaction is similar to that caused by CD4+ T cells?

Delayed-type hypersensitivity (DTH) reaction

Which antigens are most frequently recognized by alloantibodies in graft rejection?

Donor HLA molecules, including both class I and class II MHC proteins

What is indirect presentation of alloantigens?

Donor MHC molecules are captured and processed by recepient APCs that enter grafts, and peptides derived from the allogenic MHC molecules are presented in association with self MHC molecules

What drug operates in a similar mechanism as the cyclosporine-cyclophilin complex?

Drug 5K506

What is the mechanism of anti-T cell antibodies for depleting circulating T cells?

Either by activating the complement system to eliminate T cells or by opsonizing them for phagocytosis

How do T cells escape elimination by OKT3?

Endocytosis of CD3 off their surface

T or F? Hyperacute rejection by anti-ABO antibodies is common.

False, it is extremely rare now because all donor and recipient pairs are selected so they have the same ABO type

T or F? Acute rejection is either cellular or humoral, but not both.

False, typically they coexist in acute rejection

What conditions are associated with chronic rejection in liver transplants?

Fibrotic and nonfunctional bile ducts (vanishing bile duct syndrome)

What is the principal limitation of the success of bone marrow transplantation?

GVHD

What has been developed to overcome this limitation?

Human-mouse chimeric antibodies, which are less immunogenic

What is the major limitation to the use of monoclonal or polyclonal antibodies?

Humans given these agents produce anti-immunoglobulin (Ig) antibodies that eliminate the injected foreign Ig

What does the crossmatching detect?

If the patient has antibodies that react specifically with that donor's cells

Currently, hyperacute rejection of allografts, when it occurs, is usually mediated by _________ directed against protein alloantigens.

IgG antibodies

In the early days of transplantation, hyperacute rejection was often mediated by preexisting ________.

IgM alloantibodies

What are the principle agents used to treat or prevent graft rejection?

Immunosuppressive drugs that inhibit or kill T cells

What is the limitation of azathioprine?

It is toxic to precursors of leukocytes in the bone marrow and enterocytes in the gut

What is a limitation of cyclosporine?

Kidney damage

The molecules responsible for almost all strong rejection reactions are called _________.

MHC molecules

Why will transplants of most tissues between any pair of individuals be rejected?

MHC molecules, the major polymorphic targets or graft rejection, are expressed on virtually all tissues

What is the major strategy for reducing graft immunogenicity?

Minimize alloantigentic differences between the donor and recepient

How many transplantations of the kidney, heart, lung, liver, and pancreas are performed each year in the US?

More than 30,000

How does the panel reactive antibody test work?

Patients waiting for organ transplants are screened for the presence of preformed antibodies reactive with allogeneic HLA molecules prevalent in the population (resulting from previous pregnancies, transfusions, or transplantation)

What are some other antibodies used for rejection?

Polyclonal rabbit or horse antibodies specific for a mixture of human T cell surface proteins called antithymocyte globulin

What immunosuppressive drug inhibits growth factor-mediated T cell proliferation?

Rapamycin (sirolimus)

What is a graft transplanted between two genetically identical or syngeneic individuals called?

Syngeneic graft

How do alloreactive CD4+ T cells cause graft rejection?

The CD4+ helper T cells differentiate into cytokine-producing effector cells that damage grafts by cytokine-mediated inflammation

Why may indirect presentation result in allorecognition by CD4+ T cells?

The alloantigen is acquired by host APCs primarily through the endosomal vesicular pathway and is therefore presented by class II MHC molecules

What causes graft-versus-host disease (GVHD)?

The reaction of grafted mature T cells in the marrow inoculum with alloantigens of the host

What is the role of metabolic toxins (antimetabolites) in treating graft rejection?

These agents inhibit the proliferation of lymphocyte precursors during their maturation and also kill proliferating mature T cells that have been stimulated by alloantigens

What conditions are associated with chronic rejection in lung transplants?

Thickened, small airways (bronchiolitis obliterans)

What characterizes hyperacute rejection?

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

What is the transplantation of circulating blood cells or plasma called?

Transfusion

What is a heterotopic transplantation?

Transplantation in which the graft is placed in a different site

What is an orthotopic transplantation?

Transplantation in which the graft is placed into its normal anatomic location

T or F? Anti-HLA antibodies contribute significantly to allograft rejection.

True

T or F? Each allogeneic MHC molecule may give rise to multiple foreign peptides, each recognized by different T cells.

True

T or F? GVHD may also develop when solid organs that contain significant numbers of T cells are transplanted, such as the small bowel, lung, or liver.

True

T or F? In current clinical practice, episodes of acute rejection may occur at much later times, even years after transplantation, if immunosuppression is reduced for any number of reasons.

True

T or F? MHC molecules are the most polymorhphic proteins in the genome.

True

What conditions are associated with chronic rejection in kidney and heart transplants?

Vascular occlusion and interstitial fibrosis

When does graft-versus-host disease occur?

When the host is immunocompromised and therefore unable to reject the allogeneic cells in the graft

What is a graft transplanted between individuals of different species called?

Xenogeneic graft

The molecules that are recognized as foreign on allografts are called ___________.

alloantigens

Binding of antibody to endothelium activates complement, and antibody and complement products together induce a large number of changes in the graft endothelium that promote __________.

intravascular thrombosis

Many of the T cells that respond to an allogeneic MHC molecule, even on first exposure, are ________.

memory T cells

In most cases of graft-versus-host disease, the reaction is directed against __________ of the host because bone marrow transplantation is not performed when the donor and recipient have differences in MHC molecules.

minor histocompatibility antigens

The presence of large numbers of memory cells may lead to _______ outcomes of transplantation.

poor

Before modern immunosuppression, acute rejection would often begin _________ after transplantation.

several days to a few weeks

The molecules that are recognized as foreign on xenografts are called _________.

xenoantigens