Mechanisms of Immunomodulation by anti-RBC antibodies

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DESCRIPTION (provided by applicant): Chronic transfusion of red blood cells (RBCs) is essential for treating many disease states. Although blood is matched for ABO and RhD antigens, there are several hundred additional blood group antigens against which transfusion recipients can mount antibody responses. With chronic transfusion, patients may become immunized to enough clinically significant RBC antigens that essentially all available RBC units are incompatible. This requires either forgoing the beneficial and/or life saving effects of transfusion or transfusing "least incompatible" blood and risking potentially fatal hemolytic transfusion reactions. Thus, for a range of illnesses requiring chronic transfusion, alloimmunization to multiple RBC antigens can preclude the use of life saving transfusions, resulting in considerable morbidity and/or mortality. Although the use of anti-D immunoglobulin (RhIg) is best known for its high success in preventing alloimmunization of RhD- mothers to fetal RhD+ RBCs, RhIg also has considerable efficacy in preventing alloimmunization to transfusion of RhD+ RBCs to RhD- recipients. Unfortunately, no RhIg-like products are available for use against other blood group antigens (i.e. Kell, Kidd, Duffy etc.). The extension of RhIg-like therapies to such antigens would be a significant step in preventing alloimmunization in patients requiring chronic RBC transfusion therapy. The development of such reagents requires a mechanistic understanding of RhIg function. However, despite decades of confirmed efficacy, the mechanisms of RhIg remain unknown. To date, no animal model of RhIg has been described that will allow a hypothesis based approach to elucidating the mechanisms of RhIg function. We have previously described the successful generation of two murine models of alloimmunization to RBC transfusion. These models were generated using transgenic mice expressing either hen egg lysozyme (mHEL) or glycophorin A (hGPA) on RBCs. By transfusing transgenic RBCs into wild-type recipients, alloimmunization to the transgenic RBC antigens can be studied. Herein, we propose to adapt this model to the study of RhIg function, allowing an in-depth elucidation of the mechanisms by which RhIg prevents alloimmunization to RBC antigens. Central Hypothesis: Injection of antibodies to mHEL and/or hGPA will prevent subsequent immunization in mice transfused with mHEL or hGPA RBCs, with similar biological characteristics to prevention of alloimmunization to RhD by RhIg in humans. Specific Aim 1: Test the ability of anti-HEL and anti-hGPA to prevent immunization in mice following transfusion of mHEL or hGPA RBC, respectively. Specific Aim 2: Determine if transfusion of mHEL or hGPA RBC into mice treated with anti-HEL or anti-GPA, respectively, induces immunological tolerance to mHEL and hGPA antigens. PUBLIC HEALTH RELEVANCE: Chronic transfusion of red blood cells (RBCs) is essential for treating many disease states. However, transfusion recipients can mount immune responses against donor RBCs. Over time, this can result in patients who cannot receive beneficial and/or life saving transfusions, because no compatible blood is available. There is a drug that can prevent this problem in limited settings, but it is not yet broadly applicable to RBC transfusion. Ultimately, the goal of this project is to extend this drug so that it can be used to prevent immune responses against RBCs from any donor. To do this, an animal model is required. We propose to generate an animal model, which will allow a mechanistic understanding of how the existing drug works, and how we can extend its benefits to RBCs of all types. Such a model has the potential to allow improvement of existing therapies and generation of new therapies, to facilitate transfusion as a treatment for any disease that requires transfusion. Some examples include: sickle cell anemia, alpha and beta thalassemia, aplastic anemia, renal failure, myeloproliferative disorders, bone marrow and solid organ transplantation, and other chronic anemias of various etiologies.