Seminar on��Transplantation Immunology: Organ and Tissue Transplantation Immunosuppressive Agents, Immunosuppressive Therapy.

By

Mr.Pratap J. Patle

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Deptt. Of Zoology

R.T.M. Nagpur University, Nagpur

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Contents

• Introduction
• Immunology of Transplant Rejection
• Tissue and Organ Transplantation
• Immunosuppressive Agents
• Immunosuppressive Therapy
• Conclusion
• References

Introduction

• Transplantation immunology - sequence of events that occurs after an allograft or xenograft is removed from donor and then transplanted into a recipient.

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• A major limitation to the success of transplantation is the immune response of the recipient to the donor tissue.

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Types of Transplant

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• Autograft is self-tissue transferred from one body site to another in the same individual.

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• Isograft is tissue transferred between genetically identical individuals.

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• Allograft is tissue transferred between genetically different members of the same species.

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• Xenograft is tissue transferred between different species

Immunology of Transplant Rejection

Components of the Immune system involved in graft Rejection :

1) Antigen presenting cells –

• Dendritic cells
• Macrophages
• Activated B Cells

2) B cells and antibodies –

• Preformed antibodies
• Natural antibodies
• Preformed antibodies from prior sensatization
• Induced antibodies

3) T cells

4) Other cells –

• Natural killer cells
• T cells that express NK cell – associated Markers
• Monocytes/Macrophages

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The Immunology of Allogeneic Transplantation

• Recognition of transplanted cells that are self or foreign is determined by polymorphic genes (MHC) that are inherited from both parents and are expressed co-dominantly.

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• Alloantigens elicit both cell-mediated and humoral immune responses.

Recognition of Alloantigens

• Direct Presentation
• Recognition of an intact MHC molecule displayed by donor APC in the graft
• Basically, self MHC molecule recognizes the structure of an intact allogeneic MHC molecule
• Involves both CD8⁺ and CD4⁺ T cells.

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• Indirect Presentation
• Donor MHC is processed and presented by recipient APC
• Basically, donor MHC molecule is handled like any other foreign antigen
• Involve only CD4+ T cells.
• Antigen presentation by class II MHC molecules.

Activation of Alloreactive T cells and Rejection of Allografts

• Donor APCs migrate to regional lymph nodes and are recognized by the recipient’s T_H cells.
• Alloreactive T_H cells in the recipient induce generation of T_DTH cell and CTLs then migrate into the graft and cause graft rejection.

Activation of Alloreactive T cells and Rejection of Allografts

Role of CD4⁺ and CD8⁺ T Cells

• CD4⁺ differentiate into cytokine producing effector cells
• Damage graft by reactions similar to DTH
• CD8⁺ cells activated by direct pathway kill nucleated cells in the graft
• CD8⁺ cells activated by the indirect pathway are self MHC-restricted

Role of Cytokines in Graft Rejection

• IL – 2, IFN – γ, and TNF - β are important mediators of graft rejection.
• IL – α promotes T-cell proliferation and generation of T – Lymphocytes.
• IFN - γ is central to the development of DTH response.
• TNF - β has direct cytotoxic effect on the cells of graft.
• A number of cytokines promote graft rejection by inducing expression of class – I or class – II MHC molecule on graft cell.
• The interferon (α, β and γ), TNF – α and TNF - β all increases class – I MHC expression, and IFN - γ increases class – II MHC expression as well.

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Effector Mechanisms of Allograft Rejection�

• Hyperacute Rejection
• Acute Rejection
• Chronic Rejection

Hyperacute Rejection

• Characterized by thrombotic occlusion of the graft
• Begins within minutes or hours after anastamosis
• Pre-existing antibodies in the host circulation bind to donor endothelial antigens
• Activates Complement Cascade
• Xenograft Response

Hyperacute Rejection

1. Preformed Ab, 2. complement activation,

3. neutrophil margination, 4. inflammation,

5. Thrombosis formation

Acute Rejection

• Vascular and parenchymal injury mediated by T cells and antibodies that usually begin after the first week of transplantation if there is no immunosuppressant therapy
• Incidence is high (30%) for the first 90 days

Acute Rejection

1. T-cell, macrophage and Ab mediated,
2. myocyte and endothelial damage,
3. Inflammation

Chronic Rejection

• Occurs in most solid organ transplants
• Heart
• Kidney
• Lung
• Liver
• Characterized by fibrosis and vascular abnormalities with loss of graft function over a prolonged period.

Chronic Rejection

1. Macrophage – T cell mediated
2. Concentric medial hyperplasia
3. Chronic DTH reaction

Tissue and Organ Transplantation

• Today it is possible to transplant many different organs and tissues including.
• Most common transplantation is blood transfusion.
• Bone Marrow transplantation
• Organs : Heart, kidneys, pancrease, lungs, liver and intestines.
• Tissues : include bones, corneas, skin, heart values, veins, cartilage and other connective tissues.

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Most Common Transplantation�-Blood Transfusion-

Transfuse

Not transfused

Bone Marrow Transplantation

• Used for Leukemia, Anemia and immunodeficiency, especially severe combined immunodeficiency (SCID).
• About 10⁹ cells per kilogram of host body weight, is injected intravenously into the recipients.
• Recipient of a bone marrow transplant is immunologically suppressed before grafting.
• Eg. Leukemia patients are often treated with cyclo-phosphamide and total body irradiation to kill all cancerous cells.
• Because the donor bone marrow contains immunocompetent cells, the graft may reject the host, causing graft versus host disease (GVHD).

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Graft vs. Host Disease

• Caused by the reaction of grafted mature T-cells in the marrow inoculum with alloantigens of the host
• Acute GVHD
• Characterized by epithelial cell death in the skin, GI tract, and liver
• Chronic GVHD
• Characterized by atrophy and fibrosis of one or more of these same target organs as well as the lungs

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Heart Transplantation :

• First heart transplant in South Africa by Dr. Christian Barnard in 1964.
• One year survival rate is >80%.
• HLA matching is desirable but not often possible, because of the limited supply of heart and the urgency of the procedure.

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Lung Transplantation :

• First attempt in 1963 by Hardy and Co - workers.
• First successful transplantation by Toronto group in 1983.
• In conjunction with heart transplantation, to treat diseases such as cystic fibrosis and emphysema or acute damage to lungs.
• First year survival rate is about 60%.

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Kidney Transplantation :

• Diseases like diabetes and various type of nephritis can be elleviated by kidney transplantation.
• Survival rate after one year transplantation is >90%.
• 25,000 candidates are waiting for kidney transplantation.

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Liver transplantation :

• It treat congenital defects and damage from viral (hepatitis) or chemical agents. (Chronic alcoholism).
• Liver one year survival exceeds 75% and five year is 70%.

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Pancrease Transplantation :

• Offers a cure for diabetes mellitus.
• Graft survival is 72% at one year.
• Further improved if a kidney is transplanted simultaneously.
• Overall goal - to prevent the typical diabetic secondary complications.

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Skin grafting :

• It is used to treat burn victims.
• In severe burn, grafts of foreign skin may be used and rejection must be prevented by the use of immunosuppressive therapy.

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Xenogeneic Transplantation

• A major barrier to xenogeneic transplantation is the presence of natural antibodies that cause hyperacute rejection.

Immunosuppressive Agents

Immunosuppression can be brought about by 3 different ways :-

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• Surgical ablation
• Total Lymphoid Irradiation
• Immunosuppressive drugs

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Immunosuppressive Drugs

Three main immunosuppressant drugs

• Cyclosporins act by inhibiting T-cell activation, thus preventing T-cells from attacking the transplanted organ.
• Azathioprines disrupt the synthesis of DNA and RNA and cell division.
• Corticosteroids such as prednisolone suppress the inflammation associated with transplant rejection.

Immunosuppressants can also be classified depending on the specific transplant:

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• Basiliximab in combination with cyclosporin and corticosteroids, in kidney transplants.
• Daclizumab in combination with cyclosporin and corticosteroids, in kidney transplants.
• muromonab CD3 (Orthoclone OKT3) along with cyclosporin, in kidney, liver and heart transplants.
• Tacrolimus is used in liver transplants and is under study for kidney, bone marrow, heart, pancreas, pancreatic island cell, and small bowel transplantation.

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Some immunosuppressants are also used to treat a variety of autoimmune diseases:

• Azathioprine in treatment of rheumatoid arthritis , chronic ulcerative colitis but limited value.
• Cyclosporin is used in heart, liver, kidney, pancreas, bone marrow and heart/lung transplantation. Also used to treat psoriasis and rheumatoid arthritis, multiple sclerosis, diabetes and myesthenia gravis.
• Glatiramer acetate is used in treatment of relapsing-remitting multiple sclerosis.
• Mycophenolate is used along with cyclosporin in kidney, liver and heart transplants. Also used to prevent the kidney problems associated with lupus erythematosus.
• Sirolimus in combination with cyclosporin and corticosteroids, in kidney transplants. The drug is also used for the treatment of psoriasis.

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Immunosuppressive Therapy

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Monoclonal antibodies

• To suppress the activity of subpopulation of T-cells.
• To block co-stimulatory signals.
• Ab to the CD3 molecule of TCR (T cell receptor) complex results in a rapid depletion of mature T-cells from the circulation.
• Ab specific for the high-affinity IL-2 receptor is expressed only on activated T-cell, blocks proliferation of T-cells activated in response to the alloantigens of the graft.
• To treat donor’s bone marrow before it is transplanted.
• Molecules present on particular T-cells subpopulation may also be targeted for immunosuppressive therapy.
• Antibody to CD4 shown to prolong graft survival.
• Ab specific for implicated cytokine can prolong the survival of graft.

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Conclusion

• More than 50,000 people, waiting for compatible donor. For ethical an practical reasons, species closely related to human such as Chimpanzee have not been widely used.
• Xenogeneic transplantation may be major issue of research xenograft technology including genetically modified animal may become a new source of organ supply.
• Side effects of immunosuppressive agent use for graft need a change of specificity in action and avoiding general immune suppression.
• Techniques such as transgenic animal production and wide range of research in this field hope to result in opening a new window for the process of transplantation immunology.

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References

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• Immunology by – Janis Kuby
• Immunology by – Abdul Abbas
• Immunology by – Roitt
• Fundamental Immunology by – William E. Paul

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Information from –

• www.organtransplants.org
• www.transweb.org
• www.organdonor.web

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