Medical brain notes 37

  Monoclonal Antibodies in Solid Organ Transplantation INTRODUCTION   Administration of targeted immunosuppression, in the form of genetically engineered antibodies, is commonplace in solid organ transplantation. Polyclonal antibodies, such as rabbit anti-thymocyte globulin, offer global immunosuppression by target-ing several cell surface antigens on B- and T-lymphocytes. However, secondary to their broad therapeutic targets, they are associated with infection, infusion related reactions, inter-batch variability, and post-transplant malignancy. Nevertheless, polyclonal antibodies are still commonly administered for in-duction and treatment of allograft rejection and offer an important role in current solid organ transplanta-tion, which is beyond the scope of this chapter.   In an attempt to target solid organ transplant immunosuppression, monoclonal antibodies directed  against key steps in specific immunologic pathways were introduced. The first agent, muromonab-CD...

  IMMUNOLOGIC TARGETS: RATIONAL DEVELOPMENT/ USE OF MONOCLONAL ANTIBODIES IN ORGAN TRANSPLANT   The rational use of monoclonal antibodies in trans-plantation is focused on the prevention of host immune recognition of donor tissue. There are two ways in which allograft tissue can be immediately impaired secondary to the host immune response: complement-dependent antibody mediated cell lysis (antibody-mediated rejection) and T-cell-mediated parenchymal destruction leading to localized allograft inflammation and arteritis (cellular-mediated rejec-tion) (Halloran, 2004). Pre-transplant screening for antibodies against donor tissues has significantly reduced the incidence and severity of antibody-mediated rejection. However, as will be discussed, preferential destruction of cells that produce these antibodies using monoclonal technology, such as rituximab, prior to transplant has become an option for recipients with preformed alloantibodies. Prevention and treatment of cellular-med...

  Monoclonal Antibodies Administered Pre-Transplant   Immunologic barriers to solid organ transplantation are common. Improved management of end-stage organ disease has increased the number of potential organ recipients and produced a significant shortage of organs available for transplant in comparison to the growing demand. Therefore, clinicians have sought to transplant across previously contraindicated immunologic barriers. In addition, more patients are surviving through their first transplant and are now waiting for a subsequent transplant. Monoclonal antibodies are now being employed prior to trans-plant to desensitize the recipient’s immune system. Desensitization is a strategy where immunosuppres-sion is administered prior to transplant to prevent hyperacute or early rejection in patients who are known to have circulating antibodies against other human antigens. This strategy is generally reserved for patients who are “highly sensitized” during their evaluation for tr...

  Monoclonal Antibodies Administered at the Time of Transplant   Current maintenance immunosuppression is aimed at various targets within the immune system to halt propagation of signal transduction pathway. Available agents, although effective, are associated with sig-nificant patient and allograft adverse effects which are associated with long-term exposure (Table 3). The leading cause of death in non-cardiac transplant recipients is a cardiovascular event. These cardiovas-cular events have been linked to long-term corticos-teroid exposure. In addition, chronic administration of calcineurin inhibitors (cyclosporine and tacrolimus) is also associated with acute and chronic kidney dysfunction leading to hemodialysis or need for a kidney transplant. Monoclonal antibodies given at the time of transplant (induction) have been used to decrease the need for corticosteroids and allow for the delay or a reduction in the amount of calcineurin inhibitor used. Determination of the solid...

  Monoclonal Antibodies Administered Following Transplant   Monoclonal antibodies given following transplanta-t ion are u sed to t re at allograft rejection. Administration of these agents is mainly reserved for severe allograft rejection in which the immunolo-gic insult must be controlled quickly. Under normal homeostatic conditions the humoral immune system provides immediate control of infectious pathogens through secretion of antibodies. Cell mediated im-munity, in addition to fighting infections, provides surveillance against the production of mutant cells capable of oncogenesis. Interruption of either of these immune systems through the use of monoclonal antibodies places these patients at significant risk for infection and malignancy. Careful post administration assessment of infection and post-transplant malig-nancy is commonplace.

  SPECIFIC AGENTS USED IN SOLID ORGAN TRANSPLANT   Muromonab   Muromonab was the first monoclonal antibody used in solid organ transplantation. Muromonab is a murine monoclonal antibody directed against human CD3 receptor, which is situated on the T-cell antigen receptor of mature T-cells, inducing apoptosis of the target cell (Bodziak, 2003; Wilde, 1996). Cells which display the CD3 receptor include CD2, CD4, and CD8 positivelymphocytes (Ortho Biotech, 2004). Other investigators suggest that muromonab may also induce CD3 com-plex shedding, lymphocyte adhesion molecule expres-sion causing peripheral endothelial adhesion, and cell mediated cytolysis (Wilde, 1996; Ortho Biotech, 2004 Buysmann et al., 1996; Magnussen and Moller, 1994; Wong et al., 1990). Muromonab is approved for the treatment of kidney allograft rejection and steroid resistant rejection in heart transplant recipients (Ortho Biotech, 2004). Muromonab was initially employed as an induction agent for kidney tr...

  Interleukin-2 Receptor Antagonists   IL-2 antagonists were the next monoclonal antibodies to be used and were specifically developed for use in solid organ transplantation. As previously mentioned, monoclonal antibody use and development in solid organ transplantation is rational. The IL-2 receptor was targeted for several reasons. IL-2, the ligand for the IL-2 receptor, is a highly conserved protein, with only a single gene locus on chromosome 4 (Church, 2003). Animal IL-2 knockout models have decreased lymphocyte function at 2 to 4 weeks of age and early mortality at 6 to 9 weeks of age (Chen and Harrison, 2002). These models also display significantly dimin-ished myelopoesis leading to severe anemia and global bone marrow failure (Chen and Harrison, 2002). This observation confirms the significant role that IL-2 and the IL-2 receptor complex play in immunity. The function and biological effect of IL-2 binding to the IL-2 receptor was first reported by Robb and Smith in 19...

  Alemtuzumab   Recently, alemtuzumab was introduced into solid organ transplantation. Alemtuzumab is a recombinant DNA-derived, humanized, rat IgG1 k  monoclonal antibody targeting the 21 to 28 kDa cell surface protein glycoprotein CD52, which is produced in a Chinese hamster ovary suspension medium (Genzyme Corporation, 2005; Kneuchtle et al., 2004). Initially, the first anti-CD52 antibodies were developed from rat hybrid antibodies that were produced to lyse lymphocytes in the presence of complement (Morris, 2006). Campath-1M was the first agent developed. This molecule was a rat IgM antibody which produced little biological effect. In contrast, the rat IgG (Campath-1G) produced profound lymphopenia (Morris, 2006). In order to prevent the formation of antibodies against the rat IgG the molecule was humanized and called alemtuzumab or Campath-1H (Morris, 2006). The biologic effects of alemtuzumab are the same as Campath-1G, and include comple-ment-mediated cell lysis, a...

  Rituximab   Rituximab is a monoclonal antibody directed at the CD20 cell surface protein. Rituximab is currently FDA approved for the CD20 positive forms of Non-Hodgkin’s lymphoma and refractory rheumatoid arthritis. The CD20 protein is expressed on all B-cells, from pre-B-cells to activated B-cells. This protein is not expressed on hematopoetic stem cells, plasma cells, or T-lympho-cytes (Tobinai, 2003). The CD20 protein is a calcium channel and is responsible for B-cell proliferation and differentiation (Tobinai, 2003). Early monoclonal anti-bodies developed against CD20 revealed that anti-body binding did not result in modulation of activity or shedding of the surface protein, making the development of a humanized anti-CD20 antibody rational (Tobinai, 2003). Rituximab was originally developed to treat B-cell lymphomas, as the vast majority of malignant B-cells express the CD20 receptor. Following continuously infused, high doses of engineered anti-CD20 monoclonal antibodi...