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-mediated rejec-tion, therefore, is the main focus of maintenance immunosuppression and the rationale for use of monoclonal antibodies in the early post-transplant period. Cellular mediated rejection is characterized by initial recognition of donor tissue by T-cells. This leads to a complex signal transduction pathway tradition-ally described as three signals (Halloran, 2004):
· Signal 1: Donor antigens are presented to T-cells leading to activation
· Signal 2: CD80 and CD86 complex with CD28 on the T-cell surface activating signal transduction pathways (calcineurin, mitogen-activated protein kinase, protein kinase C, nuclear factor kappa B) which leads to further T-cell activation, cytokinerelease and expression of the interleukin-2 (IL-2) receptor (CD25)
· Signal 3: IL-2 and other growth factors cause the activation of the cell cycle and T-cell proliferation (Halloran, 2004)
Monoclonal antibodies have been developed against various targets within this pathway to prevent propagation and lymphocyte proliferation providing profound immunosuppression (Table 1). Monoclonal antibodies that were originally developed for treat-ment of various malignancies have also been em-ployed as immunosuppressant agents in solid organ recipients. Use of these agents must be balanced with maintenance immunosuppression to minimize the patient’s risk of infection or malignancy from over immunosuppression. Table 2 summarizes when and which monoclonal antibodies are currently used in solid organ transplantation.