Graft Rejection

,ALEXANDRIA UNIVERISTY ,FACULTY OF MEDICINE PATHOLOGY . DEPARTMENT

objectives 1.

Immune system.

2. 3. 4. 5.

Cause of graft rejection. Important definitions. Types of graft rejection. Treatment of graft rejection.

Immune System The immune system defends the body against disease. Lymphocytes are one type of white blood cell that helps the body resist infection by recognizing harmful foreign substances, such as bacteria, and eliminating them. The ability of the vertebrate immune system to distinguish self from non self depends largely on a group of protein makers (antigens) known as the major histocompatibility complex (MHC). These markers are present on the surface of every cell are slightly different in different individuals. The genes that code for these proteins are found linked together on one chromosome (chromosome 6 in humans).

In humans the MHC is called the HLA (human leukocyte antigen) group. HLA is determined by five different linked genes. These genes are all polymorphic ,within the population there are multiple alleles at each locus. Because of the polymorphism of the HLA genes, it is difficult to find identical matches among strangers. If a tissue or organ is taken from a donor and transplanted to the body of an unrelated host, several of the HLA antigens are likely to be different.The host's immune system regards the graft as foreign and launches an effective immune response called a graft rejection.T lymphocytes attack the transplanted tissue and can destroy it within a few days. The T-cells cause cells in the transplanted tissue to lyse, or produce cytokines that cause necrosis of the transplanted tissue.

• Autologous Graft = Autograft One site to another site in/on the same host • Syngeneic Graft = Syngraft Genetically identical but different individual hosts (identical twins, clones) • Allogeneic Graft = Allograft Same species but genetically different individuals (different people) • Xenogeneic Graft = Xenograft Different species Primarily use of pig heart valve in humans

Before transplants are performed, tissues from the patient and from potential donors must be typed and matched as well as possible.

GRAFT REJECTION TYPES 1.HYPERACUTE – Immediate rejection 2.ACUTE – Cellular 3.CHRONIC – Fibrosis

1-Hyperacute rejection Hyperacute rejection is a complement-mediated response in recipients with pre-existing antibodies to the donor ( ABO blood type antibodies) Hyperacute rejection occurs within minutes and the transplant must be immediately removed to prevent a severe systemic inflammatory response. Rapid agglutination of the blood occurs.This is a particular risk in kidney transplants. For other organs, hyperacute rejection is prevented by transplanting only ABO-compatible grafts. Hyperacute rejection is the likely outcome of xenotransplanted organs

2-Acute rejection Acute rejection usually begins one week after transplantation.The risk of acute rejection is highest in the first three months after transplantation. However, acute rejection can also occur months to years after transplantation. A single episode of acute rejection is not a cause for concern if recognised and treated promptly, and rarely leads to organ failure. But recurrent episodes are associated with chronic rejection .

Tissues such as the kidney or the liver which are highly vascularized (rich in blood vessels), are often the earliest victims of acute rejection. Damage to the endothelial lining of blood vessels is an early predictor of irreversible acute transplant rejection. The diagnosis of acute rejection relies on clinical data, including patient signs and symptoms, laboratory testing and a tissue biopsy. There areThree main histological features.: 1the presence of T-cells infiltrating the transplanted tissue;& may be eosinophils, plasma cells and neutrophils. 2-structural injury to the transplanted tissue; the characteristics of this injury will depend on the type of tissue being transplanted. 3- injury to the blood vessels in the transplanted tissue.

3-Chronic rejection Chronic rejection describe loss of function in transplanted organs, associated with fibrosis of the internal blood vessels of the transplanted tissue. now termed chronic allograft vasculopathy. IN chronic rejection the rejection is due to a chronic immune response against the transplanted tissue.. This usually leads to need for a new organ transplant after a decade or so.

Treatment of rejection Chronic transplant rejection is irreversible and cannot be treated effectively. The only definitive treatment is retransplantation, if necessary. This would typically be ten

years after a transplant, and this may entail returning to a transplant queue. Acute transplant rejection can be treated using chemotherapeutic drugs designed to suppress the immune system . Acute rejection is normally treated initially with a short course of high-dose corticosteroids, which is usually sufficient to treat successfully. If this is not enough, the course can be repeated or a triple therapy regimen can be used, consisting of a corticosteroid plus a calcineurin inhibitor ( Cyclosporin A – cyclic peptide that binds with cyclophilin together they inhibit calcium/calmodulin activation ) and an antiproliferative agent. Antibodies against specific components of the immune system can be added to this regimen , especially for high-risk patient.Acute rejection refractory to these treatments may require blood transfusions to remove antibodies against the transplant. Treatment is usually necessary for the life of the recipient.

IMMUNOSUPPRESSION 1. Corticosteroids

* Lysis of mature cortical T cells. * Activation of endogenous nucleases (cleave DNA). * Block cytokine gene transcription. * Inhibition of IL-1, IL-6, and TNF production.

2.Metabolic Toxins

General group of toxins that inhibit Lymphocyte growth. • Azathioprine • Cyclophosphamide • Hydroxychloroquine • Cyclosporin • Calcineurin

3.Iratiation T cells are particularly sensitive to Gamma radiation treatments.

4.Induce tolerance Multiple blood transfusions prior to transplant induces generalized tolerance. 5.Antibodies • Antibodies to T cell surface markers • Mouse derived monoclonal antibodies to CD3 • Antibodies to B cells inhibit Abs synthesis • Can also remove Ab by plasmapheresis

References •

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Aust doctors hail teen's transplant 'miracle' Sean Rubinsztein-Dunlop, ABC News (Australia), January 24,2008 Demi-Lee Brennan has changed blood types and immune system Kate Sikora, Daily Telegraph, January 25, 2008