Porth's Essentials of Pathophysiology, 4e

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Disorders of the Immune Response

C h a p t e r 1 6

Graft-Versus-Host Disease Graft-versus-host-disease (GVHD) occurs when immu- nologically competent cells or precursors are transplanted into recipients who are immunologically compro- mised. 17,18 Although GVHD occurs most often in persons who have undergone allogeneic bone marrow transplan- tation, it may also follow transplantation of organs rich in lymphoid tissue (e.g., the liver) or follow transfusions with nonirradiated blood. 2 Three basic requirements are necessary for GVHD to develop: (1) the transplant must have a functional cellular immune component, (2) the recipient tissue must bear antigens foreign to the donor tissue, and (3) recipient immunity must be compromised to the point that it cannot destroy the transplanted cells. 1,17,18 The primary agents of GVHD are the donor immunocompetent T cells derived from the donor mar- row and the recipient tissue that they recognize as foreign and react against. 2 Graft-versus-host-disease results in activation of both CD4 + and CD8 + T cells, ultimately gen- erating type IV cell-mediated DTH and CTL reactions. The greater the difference in tissue antigens between the donor and recipient, the greater the likelihood of GVHD. Graft-versus-host-disease can occur as an acute or chronic reaction. Acute GVHD , which develops within days to weeks after transplantation, involves the epithe- lial cells of the skin, liver, and gastrointestinal tract. 2 The organ most commonly affected in acute GVHD is the skin. There is development of a pruritic, maculopapular rash, which begins on the palms and soles and frequently extends over the entire body, with subsequent desquama- tion (sloughing off skin). Involvement of the gastrointesti- nal tract usually parallels the development of skin and liver involvement. Gastrointestinal symptoms include nausea, bloody diarrhea, and abdominal pain. Graft-versus-host- disease of the liver is heralded by painless jaundice, hyper- bilirubinemia, and abnormal liver function test results. Liver involvement can progress to development of veno- occlusive disease, drug toxicity, viral infection, iron over- load, extrahepatic biliary obstruction, sepsis, and coma. 19 Chronic GVHD may follow acute GVHD or it may develop insidiously. Persons in whom chronic GVHD develops are profoundly immunocompromised, and they develop skin lesions resembling systemic sclero- sis (discussed in Chapter 44) and manifestations mim- icking other autoimmune diseases. As a result of the severely compromised immune system, recurrent and life-threatening infections are common.

months or even years later, after the discontinuation of immunosuppressants in the post-transplant period. Before modern immunosuppression, acute rejection would often begin several days to a few weeks after transplantation. The delayed time of onset of acute rejec- tion reflects the time it takes for the recipient’s immune system to generate T cells and antibodies against the graft. 1 In kidney transplantation it is characterized by abrupt onset of kidney failure, which may be associated with fever and graft tenderness. Acute rejection most typically involves both cell-medi- ated and humoral mechanisms of tissue damage. In acute cell-mediated rejection the activated T cells cause direct lysis of graft cells and recruit and activate inflammatory cells that injure the graft. Acute antibody-mediated or humoral mechanisms involve blood vessel damage and intravascular thrombosis that leads to graft destruction. Chronic Rejection Chronic rejection develops insidiously over months and years and may or may not be preceded by episodes of acute rejection. In recent years, acute rejection has been significantly controlled by immunosuppressive therapy, and chronic rejection has emerged as an important cause of graft rejection. In kidney transplantation there are signs of progressive kidney failure. The dominant lesion in chronic rejection is arte- rial occlusion resulting from the proliferation of vas- cular smooth muscle cells, with graft failure resulting from ischemic damage. These arterial changes are often referred to as graft vasculopathy or accelerated graft arteriosis. 1 The actual mechanism of this type of response is unclear but may include release of cytokines that stimulate proliferation of vascular endothelial and muscle cells; repair with fibrosis after repeated bouts of acute antibody-mediated or cellular rejection; and toxic effects of immunsuppressive drugs. 1 Transplantation of Hematopoietic Cells Bone marrow transplantation is increasingly being used as therapy for hematopoietic and some nonhema- topoietic malignancies, aplastic anemia, and immuno- deficiency disorders. Hematopoietic stem cells can be collected from donor bone marrow or peripheral blood. Stem cell aspiration from the bone marrow is the most common form of allograft collection. Peripheral blood offers a less-invasive method for obtaining stem cells. Hematopoietic growth factors, such as granulocyte colony-stimulating factor, often are used to induce stem cells to move out of the bone marrow into the blood. Before either bone marrow or peripheral blood stem cells are infused, recipients receive pretreatment condi- tioning regimens (e.g., total-body irradiation or treat- ment with cytotoxic drugs) to destroy malignant cells (e.g., in leukemia) and to create a graft bed. Rejection of the allogeneic bone marrow transplant appears to be mediated by a combination of reactive T cells and natural killer (NK) cells that are resistant to radiation therapy and chemotherapy. 2

SUMMARY CONCEPTS

■■ Transplantation involves taking cells, tissues, or organs, called a graft, from one individual (a donor) and placing them into another individual (recipient). A major barrier to transplantation is the process of rejection in which the recipient’s immune system recognizes the graft as foreign and attacks it.

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