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Organ Transplantation

Autoimmune Disorders

Immunomodulating Drugs

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Antibodies as Immunosuppressive Drugs

  • Overview

    • Increased antibody purity/specificity used for immunosuppression due to:

      •  Hybridoma method -- fusing antibody-forming cells to immortal plasmacytoma cells

      •  Allows for mass culture antibody production

  •  Antilymphocyte and Antithymocyte Antibodies

    • Antisera against lymphocytes -- heterologous antilymphocyte globulin (ALG)

    • Organ transplantation programs use:

      •  antilymphocyte globulin (ALG)

      •  antithymocyte globulin (ATG)

      •  monoclonal anti-T cell antibodies

  •  Antilymphocyte antibodies:

    • Act on small, long-lived peripheral lymphocytes {circulating between lymph and blood}

    • Continued administration: depletion of:

      •  "thymus-dependent" lymphocytes from lymphoid follicle cuffs

    • Mechanism:

      •  antilymphocyte antibodies bind to T-cell surface

      •  induced immunosuppression

      •  Opsonization + phagocytosis of antibody-bound cells: hepatic mediation

      •  Cytotoxic destruction of antibody-bound cells: spleen-mediated (serum complement involvement) for poly clonal preparations

      •  Antibody binding may also block immune function by:

        • altering membrane surface expression of molecules important for lymphocyte function

        • example -- monoclonal antibody against CD3-T cell receptor complex.

    • Consequences of destruction/inactivation of T cells:

      •  degradation of delayed hypersensitivity and cellular immunity

      • humoral antibody formation: intact

      • antibodies (polyclonal/monoclonal) -- most selective means of modulating immune response;

        •  particularly important in organ transplantation

  • Management of Transplantation

    •  ALG + monoclonal antibodies:

      •  useful in treating initial rejection by inducing immunosuppression

      •  useful in treating steroid-resistant immunorejection

    • ALG- usually administered with prednisone + azathioprine

    • ALG plus monoclonal antibodies:

      •  used early following kidney transplantation in order to avoid early use of cyclosporine (enhanced cyclosporine- nephrotoxicity when used immediately after transplantation)

    • ALG: also used in recipient preparation for bone marrow transplant

      •  large dose ALG 7-10 days before transplant

      •  residual ALG: kills T cells in the donor-marrow-graft

        •  reduction in likelihood of severe graft-versus-host syndrome

  •  ALG: adverse effects

    • injection site: local pain/erythema

    • anaphylactic/serum sickness reactions

    • histiocytic lymphoma in the buttock (site of ALG injection)

    • increased cancer incidence and kidney transplant patients (2% in long-term survivors)

      • may be secondary to immunosuppression against oncogenic viruses

  •  Clinical Trials/Special Uses:

    • murine (mouse) monoclonal antibody (OKT3) -- directed against CD3+ on human thymocyte and T cell surfaces may help manage renal transplant rejection

      •  OKT3: marketed for renal allograph rejection crisis

    • ricin-conjugated murine monoclonal antibody -- ongoing clinical trials:

      •  apparently potent in reversing graft-versus-host syndrome after allogenic bone marrow transplantation

  • Immune Globulin Intravenous (IGIV)

    • Intravenous use: polyclonal human immunoglobulin

    • no specific antigen target

    • immunoglobulin preparation: derived from thousands of healthy individuals

    • Expectation: a "normalizing" effects on patient's immune system

    • Clinical Applications:

      • asthma

      • autoimmune disorders

      • Kawasaki syndrome

        • reduces systemic inflammation

        • prevents coronary artery aneurysms

      • subacute lupus erythematosus

      • refractory idiopathic thrombocytopenic purpura

    • Suggested Mechanisms:IGIV

      • reduction of helper T cells

      •   increase in suppressor T cells

      • reduced immunoglobulin production

      • reduced idiotypic-idiotypic interaction with "pathologic antibodies"

  • Rho(D) immune globulin micro-dose

    • Prevention of Rh hemolytic disease of the newborn

    • Rationale:

      •  a primary antibody response to a foreign antigen-- blocked if the specific antibody to that antigen is administered passively at the time of antigen exposure

    • Composition: Rho(D) immune globulin:

      • concentrated solution (15%) of human IgG with a higher titer of antibodies against the Rho(D) red cell antigen

    • Process leading to Rh hemolytic disease in the newborn:

      1.  Rh-negative mothers are sensitized to the D antigen at birth of Rho(D)-positive or Du-positive infants (fetal red cell's may leak into the mother's bloodstream.

        • {sensitization may also occur with miscarriages/ectopic pregnancies}

      2.  Subsequent pregnancies: maternal antibody against Rh-positive cells to the fetus during the third trimester erythroblastosis fetalis -- hemolytic disease of the newborn

      3.  Upon Rho(D)-administration to the mother within three days after the birth of Rh-positive baby, the mother's own antibody responds to the foreign Rho(D)-positive cells will be suppressed

        •  Following this treatment: Rh hemolytic disease has not been reported to occur in subsequent pregnancies.

        •  Successful prophylaxis requires:

          1. mother must be Rho(D)-negative

          2. mother must be Du-negative

          3. mother must not be already immunized to Rho(D) factor

Primary Source: Barbuto, J.A.M, Akporiaye, E.T. and Hersh, E.M. Immunopharmacology, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 916-940
Haynes, B. F., Fauci, A.S. Disorders of the Immune System, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 1753-1776.
Carpenter, C. B. The Major Histocompatibility Gene Complex, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 1777-1782.
Cooper,M.D, and Lawton III, A. R. Primary Immune Deficiency Diseases, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 1783-1791.
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