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Organ Transplantation

Graft Rejection
    Cellular Mechanisms
    Molecular Mechanisms

Immunsuppressive Agents
    Corticosteroids
    Calcineurine Inhibitors
    Antiproliferative Agents
    Monoclonal Antibodies
    Polyclonal Antibodies
    Side Effects       

Immunotherapy
    Inductive Therapy
    Maintenance Therapy
    Episodic Treatment

Current Areas of Research
    New Drugs
    Drug Efficacy
    Alternative Therapies
        Tolerance
        Tissue Engineering
        Xenotransplantation

Glossary of Terms
References

TOLERANCE

Tolerance refers to a state where adverse immune response to transplant antigens is eliminated while the rest of the immune system remains intact. Tolerance can be achieved through lymphocyte anergy. Anergy is a situation in which the lymphocytes specific for transplant antigens are unable to respond effectively or potential transplant-specific lymphocytes are deleted before having a chance to mature and circulate.

Effector mechanisms of lymphocytes can be suppressed in many different ways. Possibilities include suppression of appropriate APC derived co-stimulatory signals and obstruction of pathways through which rejection occurs. The latter is the ideology behind many existing immunosuppressants - they work by simply handicapping the immune system's ability to react towards what it views as foreign. Suppression of appropriate co-stimulatory signals is an active area of pharmaceutical research.

The second method of inducing tolerance is through clonal deletion of cells reactive to the foreign graft. The immune system is equipped with a mechanism for ensuring lymphocytes are not self-reactive. Self-reactivity is a condition where lymphocytes are specific for antigens that are normally occurring in the body. The immune system simply tests for and deletes self-reactive lymphocytes before maturity in a process known as negative selection.

With this idea, one proposed possibility to achieve transplant tolerance according to Megan Sykes of Harvard Medical School (Boston, MA) is by returning the immune system to an infant-like state before transplanting an organ into a patient. This could be done by irradiating the thymus and administering anti-CD4 and anti-CD8 (characteristic markers of T and B cells). This would theoretically collapse the immune system. Bone marrow cells from the donor would then be infused into the recipient's bloodstream. When the hematopoietic cells in the recipient restore the immune system, antigens encountered (including foreign antigens from the graft) will be viewed by the new immune system as self (a normally occurring antigen in the body), and reactive lymphocytes will be deleted naturally by the body's own negative selection mechanism.

In fact, Sykes was able to demonstrate induced tolerance of mice to pig skin grafts with this method. In this study, the immune system was not completely obliterating the recipients' circulating immune cells.

Another possible way of inducing tolerance includes taking advantage of the suppressor T cell (or Ts cell). This a population of T cells that is postulated to be distinct from TH and TC cells. In contrast to the other two subgroups of T cells, Ts cells work to suppress the humoral and cell-mediated branches of the immune system in an antigen-specific manner. Therefore, Ts cells specific for transplantation antigens have the potential to restrain, and possibly overpower, immune responses against foreign grafts.

Drug Therapy Research
New Drugs Drug Efficacy
Alternate Therapies
Tolerance Tissue Engineering Xenotransplantation