Increased rates of bone marrow transplant (BMT) graft rejection are observed in patients whose illnesses necessitate chronic transfusion prior to BMT, such as sickle cell disease, thalassemia, or aplastic anemia. Because BMTs in this setting are routinely HLA matched, any immunization responsible for increased rejection is likely against minor histocompatibility antigens (mHAs). It has been assumed that contaminating leukocytes in red blood cell (RBC) units are the main source of immunization to mHAs. However, we have recently reported that antigens on donor RBC are presented in the MHC class I pathway of recipient antigen presenting cells, resulting in activation and expansion of recipient CD8+ T cells specific for donor mHAs. Since human hematopoietic progenitor cells express many of the known mHAs, this observation provides a mechanism by which chronic transfusion of even stringently leukoreduced RBC may result in sufficient mHA immunization to increase the frequency of BMT rejection. Amongst the most potent and prevalent mHAs are male associated antigens (H-Y). It has been demonstrated that multiply transfused females both have anti-H-Y specific T cells that are not detected in untransfused females, and reject bone marrow from male donors with a greater frequency than they reject bone marrow from female donors. However, multiply transfused males reject bone marrow from male and female donors with equal frequency. Thus, there is circumstantial evidence that immunization to H-Y from chronic transfusion contributes significantly to BMT rejection in the non-malignant setting, but this notion has not been rigorously tested. Central Hypothesis: Transfusion of leukoreduced RBC from male donors into female recipients results in immunization against H-Y mHAs that is sufficient to cause increased rates of BMT rejection.
Specific Aim 1 -Test the immunogenicity of male-to-female RBC transfusion and its functional effects upon BMT rejection. Using a murine model of male-to-female transfusion of leukoreduced RBC we will determine: the extent of immunization to H-Y by transfusion of male RBC and the effect of such immunization upon subsequent BMT rejection.
Specific Aim 2 - Determine the extent of alloimmunization to H-Y antigen in human transfusion recipients receiving leukoreduced RBC products. By analyzing transfusion patients at Emory, we will determine the extent to which females receiving leukoreduced RBC from male donors are immunized to H-Y antigens. ? ? ?
| Desmarets, M; Mylvaganam, G; Waller, E K et al. (2011) Minor antigens on transfused RBCs crossprime CD8 T cells but do not induce full effector function. Am J Transplant 11:1825-34 |
| Desmarets, Maxime; Cadwell, Chantel M; Peterson, Kenneth R et al. (2009) Minor histocompatibility antigens on transfused leukoreduced units of red blood cells induce bone marrow transplant rejection in a mouse model. Blood 114:2315-22 |
