MICROCHIMERISM IN TRANSFUSION MEDICINE AND ORGAN TRANSPLANT REJECTION

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Microchimerism (MC) occurs following hematopoietic stem cell and solid organ transplantation , pregnancy, pregnancy and blood transfusion. MC may aid in establishing tolerance required for successful pregnancy or organ transplantation, and may be etiologically related to diverse pathological conditions. In this project, we have focused on the development of sensitive molecular techniques uniquely adapted to the detection and characterization of MC in leukocytes, plasma and serum. We have applied these techniques prospectively to investigate MC following transfusion. Our findings indicate a spectrum of donor leukocyte (DL) survival ranging from a prompt and complete clearance in transfused patients with sickle cell disease and HIV to a high-level multi- lineage chimerism persisting months to years in some patients transfused for trauma. To expand MC investigations using repository samples in specific clinical settings (immune cytopenias, autoimmune diseases, maternal-fetal interface), we have developed and begun to apply a MC screening strategy that requires neither prospective patient follow-up nor knowledge of the chimeric genotype. To understand the recipient and blood product characteristics influence DL survival, we have established a murine transfusion model. We plan to pursue the following 4 aims during the renewal phase of this grant: murine transfusion model. We plan to pursue the following 4r aims during the renewal phase of this grant: 1. Determine the prevalence, magnitude, clinical significance, and factors associated with the DL MC observed in transfused trauma patients. 2. Determine the prevalence, magnitude, and significance of microchimerism in immune cytopenias. 3. Investigate the prognostic value of chimeric donor organ-derived DNA in serum/plasma as marker of graft rejection patients with solid organ transplants. 4. Utilize a panel of knockout mice in our murine transfusion model to characterize elements of the immune system that contribute to extended DL survival in syngeneic (MHC-matched) versus allogeneic immune system that contribute to extended DL survival in syngeneic (MHC- matched) versus allogeneic (MHC-mismatched) transfusions. These studies should establish the prevalence and etiological role of MC in several transfusion-related disorders, and elucidate the immunological mechanisms underlying clearance of transfused leukocytes. Documentation of a role for organ-derived DNA as a predictive marker of graft rejection could have major impact in clinical transplantation.