Transplant Rejection

Transplantation of Solid Organs :Mechanisms Involved in Rejection : The antigens responsible for rejection

in humans are those coded by genes of HLA ( Human Leukocyte Antigen ) system [ also known as MHC ( Major Histocompatibility Complex ) ] which are present on short arm of chromosome 6 .

HLA genes are highly polymorphic.

Any two individuals (other than identical twins) will express some HLA proteins that are different (allogeneic) .

Thus, the recipient recognize them as foreign and attack them.

Rejection is a complex process in which both cell-mediated immunity and circulating antibodies ( Humoral immunity ) play a role.

T Cell-Mediated Reactions:called cellular rejection, induced by two pathways : Direct pathway: Mediated by CD8+ T cells (Cytotoxic T Lymphocyte -CTL ). Recipient CD8+ T cells recognize antigens of graft donor

presented by donor antigen-presenting cells found in the graft.

CD8+ T cells recognize class I MHC antigens. CD8+ T cells, then differentiated into mature CD8+ T cells

dependent on release of cytokines such as IL-2 from CD4+T helper cells.

Once mature CD8+ T cells are generated, they kill grafted tissue by mechanisms already discussed.

Indirect pathway : Mediated by CD4+ T lymphocytes( Helper T cell) . Recipient CD4+ T lymphocytes recognize antigens of

graft donor after they are presented by recipient's own antigen-presenting cells .

CD4+ T cells recognize class II MHC antigens ,and the result is delayed hypersensitivity type of reaction.

It is postulated that direct pathway is major pathway in acute cellular rejection, while indirect pathway in chronic rejection. However, this separation is not absolute.

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Antibody-Mediated Reactions:called humoral rejection, and take two forms: Hyperacute rejection : occurs when preformed antidonor antibodies are

present in circulation of recipient. rejection occurs immediately after transplantation the circulating antibodies deposit rapidly on vascular

endothelium of grafted organ. Complement fixation occurs resulting in thrombosis

of vessels in graft, and ischemic death of graft.

Acute humoral rejection: In recipients not previously sensitized to

transplantation antigens, exposure to class I and class II HLA antigens of donor may evoke antibodies.

The antibodies formed, cause injury by several mechanisms, including complement-dependent cytotoxicity, inflammation, and antibody-dependent cell-mediated cytotoxicity.

The initial target of these antibodies is graft vasculature. Thus sometimes referred to rejection vasculitis.

Morphology of Rejection Reactions :Rejection reactions are classified as hyperacute, acute, and chronic. Hyperacute Rejection: occurs within minutes or hours after transplantation. hyperacutely rejecting kidney rapidly becomes

cyanotic, mottled, and flaccid and may excrete few drops of bloody urine.

There is a rapid accumulation of neutrophils within arterioles, glomeruli, and peritubular capillaries.

Subsequently, these changes become diffuse and intense, the glomeruli undergo thrombotic occlusion of capillaries, and fibrinoid necrosis occurs in arterial walls.

Acute Rejection: This may occur within days of transplantation in

untreated recipient , or may appear months or even years later after immunosuppression has been terminated.

acute graft rejection is a combined process in which both cellular and humoral tissue injuries contribute.

Histologically, humoral rejection is associated with vasculitis, whereas cellular rejection is marked by interstitial mononuclear cell infiltrate.

Chronic Rejection: In recent years, acute rejection has been significantly

controlled by immunosuppressive therapy, and chronic rejection has become an important cause of graft failure.

Patients with chronic rejection present clinically with progressive rise in serum creatinine over a period of 4 to 6 months.

Chronic rejection is dominated by vascular changes, interstitial fibrosis, and tubular atrophy with loss of renal parenchyma .

The vascular changes consist of dense, obliterative intimal fibrosis, principally in renal cortical arteries.

Transplantation of Hematopoietic Cells : Use of hematopoietic cell transplants for:

hematologic malignancies; certain nonhematologic cancers; aplastic anemias; and certain immunodeficiency states.

Hematopoietic stem cells are usually obtained from bone marrow , but may also be harvested from peripheral blood after they are mobilized from bone marrow by administration of hematopoietic growth factors.

In most conditions in which bone marrow transplantation is indicated, the recipient is irradiated with lethal doses or receive chemotherapy either to destroy the malignant cells (e.g., leukemias) ; or to create a graft bed (e.g., aplastic anemias).

Three major problems arise in bone marrow transplantation:

Graft-versus-host (GVH) diseaseTransplant rejectionImmunodeficiency

GVH disease: occurs in any situation in which immunologically

competent cells or their precursors of donor are transplanted into immunologically crippled recipients.

the transferred cells recognize alloantigens in the recipients .

GVH disease occurs most commonly in setting of allogeneic bone marrow transplantation; but may also follow transplantation of solid organs rich in lymphoid cells (e.g., liver) .

Recipients of bone marrow transplants are immunodeficient because of either their primary disease or prior treatment of disease with drugs or irradiation.

When such recipients receive normal bone marrow cells from allogeneic donors, the immunocompetent T- cells present in donor marrow recognize recipient's HLA antigens as foreign and react against them.

Both CD4+ and CD8+ T cells recognize and attack the recipient's tissues.

Acute GVH disease: occurs within days to weeks after allogeneic bone

marrow transplantation. Although any organ may be affected, the major clinical

manifestations result from involvement of epithelia of skin, liver, and intestines.

Involvement of skin in GVH disease is manifested by a generalized rash.

Destruction of small bile ducts gives rise to jaundice. Mucosal ulceration of the gut results in bloody

diarrhea.

Chronic GVH disease: may follow the acute syndrome or may occur

insidiously. These patients have extensive cutaneous injury, with

destruction of skin appendages and fibrosis of dermis. The changes may resemble systemic sclerosis .

Chronic liver disease manifested by cholestatic jaundice .

Damage to gastrointestinal mucosa may cause esophageal strictures.

Transplant rejection: The mechanisms responsible for rejection of allogeneic

bone marrow transplants are poorly understood. It seems to be mediated by NK cells and T cells that

survive in the irradiated recipient. Immunodeficiency: Is a frequent accompaniment of GVH disease. Affected individuals are profoundly immunosuppressed

and are easily infected. Although many organisms may infect patients, infection

with cytomegalovirus is particularly important. Cytomegalovirus-induced pneumonitis can be fatal .

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