Overview

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

  •  Hybridoma method involves 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"

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 ® to the fetus during the third trimester ®erythroblastosis fetalis -- 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 responds 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