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The Pharmacology of Antibodies and Transplantation

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Elizabeth Sarmiento
University Hospital Gregorio Maroñon
Madrid, Spain

A major advance in the description of the chemical structure of antibodies was the discovery of the antibody light chain in the early 1960s by Gerald Edelman and Joseph Gally, who realized that these proteins were the same as the Bence-Jones protein described in 1845 by Henry Bence Jones. At around the same time, Rodney Porter characterized the antibody-binding (Fab) and antibody Fc regions of IgG. In 1972, the Nobel Prize in Physiology or Medicine was shared by Edelman and Porter for their discoveries on the chemical structure of antibodies.

Antibodies play a dual role in heart and lung transplantation. First, they are important mediators of humoral immunity against infection. At the majority of centers, we only base our assessment of CMV infection risks on donor and recipient anti-CMV IgG status. Some centers measure IgG levels to assess the risk of severe infection in both types of transplant. Second, antibodies are critical mediators of allograft immune responses. Antibody-mediated rejection is still a major barrier for long-term survival in both heart and lung recipients.

Antibodies are widely used in all kinds of immune-based methodologies that are necessary for monitoring transplant recipients. The Nobel Prize in Physiology or Medicine 1984 was awarded jointly to Niels K. Jerne, Georges J.F. Köhler and César Milstein "for theories concerning the specificity in development and control of the immune system and the discovery of the principle for production of monoclonal antibodies."

Monoclonal antibodies are particularly good diagnostic reagents because of their exquisite specificity. They generally show higher specificity than polyclonal antibody mixtures and are widely used in the monitoring of transplant recipients. Antibodies can be applied in a variety of assay formats to assess the presence or absence of a particular substance, the amount present and localization within tissues as well as the expression of lymphocyte markers. Antibody-based approaches are used to assess cytotoxic anti-HLA and non-HLA antibodies as well as in the assessment of lymphocyte subsets, humoral immunity factors, immunosuppressive drug levels and diagnosis of infections or antibody mediated rejection.

IgG and specific antimicrobial antibodies can be replaced using intravenous or subcutaneous immunoglobulins in patients with secondary antibody deficiency after heart or lung transplantation. Specific anti-CMV immunoglobulins are used in selected settings by some centers to prevent or treat CMV disease. High doses of intravenous immunoglobulin is a therapeutic strategy for desensitization in patients with high titer anti-HLA antibodies.

Monoclonal antibodies were first produced from the fusion of murine B lymphocytes and myeloma cells. Subsequent advances in technology allowed for humanized monoclonal antibodies, whose pharmacokinetic properties differ from those of murine monoclonal antibodies in humans. Current major therapeutic applications of monoclonal antibodies include cancer, chronic inflammatory disease, infection, and transplantation. In addition, monoclonal antibodies constitute the largest and fastest growing sector of the biological pharmaceutical industry. In heart and lung recipients, monoclonal antibodies are used for induction of immunosuppression and treatment of rejection or post-transplant lymphoproliferative disorders, as well as in desensitization protocols.

Owing to their mechanism of action, monoclonal antibodies are associated with a unique spectrum of immune-mediated efficacy mechanisms and adverse event profiles. The potential role of pharmacological monitoring of monoclonal antibody levels (pharmacokinetics) and for detection of the development of anti-drug antibodies is under evaluation in specific immune diseases. Several issues remain to be resolved with respect to defining precise indications, dosing, monitoring and optimal duration of therapy with these drugs. ■

Disclosure Statement: The author has no conflicts of interest to disclose.

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