• Antibodies as Immunosuppressive Drugs

  • Overview

  • Antilymphocyte and Antithymocyte Antibodies

  • Organ Transplanation

  • Antilymphocyte Antibodies (ALG)

  • Mechanisms

  • Consequences of destruction/inactivation of T cells

  • Transplantation

  • ALG-Adverse Effects

  • Clinical Trials/ Special Uses

• Immune Globulin Intravenous (IGIV)

  • Clinical Applications

  • Suggested Mechanisms

• Rh_o(D) immune globulin micro-dose

  • Prevention of Rh hemolytic disease in the newborn

  • Composition: Rh_o(D) immune globulin

  • Process leading to Rh hemolytic disease in the newborn

• Clinical Uses: Immunosuppressive Drugs

  • Overview

  • Three Primary Uses

  • Summary of Clinical Uses of Immunosuppressive Agents

Organ Transplantation

• Tissue Typing

• HLA haplotype system

• MLC system

• Value: good histocompatibility

• Primary Renal Disease

  • Factors important for transplantation success

• Bone Marrow Transplantation:

  • aplastic anemia

  • resistant acute leukemia

  • SCID (severe, combined immunodeficiency syndrome)

• Cyclosporine

Autoimmune Disorders

• Overview

  • Remissions

  • Improvement

  • Idiopathic aplastic anemia

  • Mechanism of Drug Action

Immunomodulating Drugs

• Rationale

• Potential Clinical Uses

• Current Drugs (approved and investigational)

• Thymosin

  • DiGeorge's syndrome

• Thymosin Derivatives

• Cytokines

  • Potential Clinical Uses

  • Interferon (IFN)-a

  • Interferon (IFN)-b

  • Interferon (IFN)-g

  • IL-2

  • Levamisole

  • Roquinimex -- investigational

  • BCG (Bacille Calmette-Guerin)

  • Other Immune modulators-investigational

• Cancer Immunotherapy

  • Current Approaches

  • FDA approved immunotherapeutic agents (1998)

  • Current FDA approved immunotherapeutic agents

  • Gene Therapy

    • Purpose

  • Management of Immunologic Disease

    • SCID

  • Approaches for gene therapy and management of cancer

• Gene Therapy

  • Purpose

  • Management of immunologic disease -- Example:

    • severe combined immunodeficiency syndrome (SCID) -- ADA deficiency

    • Approaches for gene therapy and management of cancer

• Immunologic Reactions to Drugs and Drug Allergy

  • Drugs causing true allergic reactions

  • Allergic Drug Reactions: characteristics

• Immune-mediated Drug reactions: Different mechanisms: Four types

  • Type I: IgE-mediated

  • Type II: Complement-dependent

  • Type III: - Serum Sickness

  • Type IV: cell-mediated allergy

• Immediate (Type I) Drug Allergy: Mechanisms

  • Drug = Hapten

  • Acute allergic reaction sequence

  • Drug Treatment

    • Prednisone

    • Reduced mediator release

    • Antihistamines

    • Corticosteroids

    • Cromolyn

    • Ketotifen

    • Drug Desensitization

• Type II Autoimmune Drug Reactions

  • Examples

    • systemic lupus erythematosus

    • "lupoid hepatitis"

    • autoimmune hemolytic anemia

    • thrombocytopenic purpura

    • agranulocytosis

• Serum sickness and Vasculitic (Type III) Reactions

  • Clinical Characteristics

  • Immune Vasculitis

  • Erythema multiforme

  • Stevens-Johnson Syndrome

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Antibodies as Immunosuppressive Drugs

• Overview

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

    •  Hybridoma method involves fusing antibody-forming cells resulting in 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 would be 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) represents the 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"

• Rh_o(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: Rh_o(D) immune globulin:

    • Concentrated solution (15%) of human IgG with a higher titer of antibodies against the Rh_o(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 Rh_o(D)-positive or D^u-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 in the fetus during the third trimester causing erythroblastosis fetalis, a hemolytic disease of the newborn.

    3.  Upon Rh_o(D)-administration to the mother within three days after the birth of Rh-positive baby, the mother's own antibody response to the foreign Rh_o(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 Rh_o(D)-negative

         2. Mother must be D^u-negative

         3. Mother must not be already immunized to Rh_o(D) factor