Prevention of Platelet Alloimmunization by Costimulatory Blockade

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DESCRIPTION (provided by applicant): Transfusion of platelets is a potentially life-saving therapy to maintain hemostasis in patients with severe thrombocytopenia. One of the main impediments to ongoing platelet transfusions is humoral immunization to platelet alloantigens, predominantly HLA antigens (MHC class I). Once alloantibodies have been formed, HLA incompatible platelets can be rapidly cleared by the recipient, resulting in little or no increase n platelet counts and thus essentially no therapeutic benefit. If a patient generates alloantibodies against multiple HLA epitopes, then finding compatible platelets can become difficult, and in many cases impossible. With alloimmunization to multiple HLA types, platelets can cease to be a viable therapy for thrombocytopenia. For patients who only need transient support with platelet transfusion, alloimmunization is not typically a serious problem; however, in patients who require ongoing therapy, anti-HLA antibodies can eliminate a life-saving therapy for which there is typically no viable substitute. In addition to rendering platelet transfusions ineffective the induction of anti-HLA antibodies can also complicate subsequent transplantation. As platelet transfusions are given to some patient populations as support while they are awaiting organ transplantation, induction of anti-HLA antibodies has an additional negative impact on this population, both from the standpoint of complicating the transplant and also potentially moving the patient down the waiting list for donor organs. The implementation of filter leukoreduction has decreased rates of alloimmunization to platelet transfusion, but residual rates remain at approximately 20%, with 1 in every 5 transfusion recipients becoming alloimmunized. Thus, additional interventions are required to reduce alloimmunization rates. Co-stimulatory blockade is a strategy to prevent alloimmunization, which has now come to fruition with the FDA approval of CTLA4-Ig. This grant application is a pre-clinical effort to begin translation of CTLA4- Ig for use in preventing alloimmunization to transfused platelets. This approach would not be used in the general population, but focused on select patient populations who are particularly vulnerable to HLA alloimmunization (patients requiring ongoing platelet transfusion and/or awaiting transplantation). We have developed a murine model of alloimmunization to transfusion of filter leukoreduced platelets. In this system, CTLA4-Ig abrogates alloimmunization and prevents recipients from becoming refractory to platelet transfusion. The model system has been engineered to have sufficient tools to allow detailed mechanistic elucidation of CTLA4-Ig function. The proposed studies are a hypothesis driven effort designed to both generate basic understanding of the immunology of platelet alloimmunization and CTLA4-Ig mechanisms of action, but with a distinct focus on pre-clinical issues necessary for subsequent human trials of CTLA4-Ig therapy to prevent alloimmunization to transfused platelets.