Allosensitization

Abstract: Presentation of alloantigens by host cells has been examined in vivo by means of a murine cell transfer system. Primary (1 degree) hosts were activated by the i.p. administration of allogeneic spleen cells and their spleen or peritoneal cells were transferred into syngeneic secondary (2 degrees) hosts 3 days later. Sensitization of 2 degrees hosts was assessed by their ability to reject donor strain skin grafts prematurely. The transferred cells were routinely depleted of T lymphocytes. We show that (a) 5 X 10(7) spleen and 3 X 10(6) peritoneal cells consistently caused marked accelerated graft rejection; (b) this effect was antigen specific and observable in all strain combinations studied; (c) it was caused by the active sensitization of 2 degrees hosts, but not by contaminating donor strain cells; (d) the cells involved were plastic adherent and viability was not a requirement; and (e) both class I and II, but not minor, histocompatibility antigens played a role in this model. We conclude that presentation of alloantigens by host antigen-presenting cells can be a potent route of allosensitization.

Abstract: Immunological recognition of foreign cells is a primary concern in both transfusion and transplantation medicine. Our unique approach to this problem is to globally camouflage the surface of the foreign cell using nonimmunogenic, long chain polymers such as methoxypoly(ethylene glycol) [mPEG]. mPEG-modification of red blood cells effectively attenuates both antibody binding to surface epitopes and decreases the inherent immunogenicity of foreign, even xenogeneic red cells. These cells exhibit normal structural and functional characteristicsin vitro and exhibit normal in vivo survival in animal models. Pegylation of white blood cells (particularly antigen presenting cells and T lymphocytes) surprisingly prevents recognition of foreign class II molecules and prevents T cell proliferation in response to foreign MHC molecules. Potential applications for the covalent binding of nonimmunogenic, long chain polymers (e.g., PEG) to intact cells include, but are not limited to: 1) derivatized RBC to diminish transfusion reactions arising from sensitization to minor blood group antigens (allosensitization) in the chronically transfused (e.g., sickle and thalassemia patients); 2) use of mPEG modification of "passenger" lymphocytes to prevent immune recognition and graft versus host disease; and 3) derivatization of the vascular endothelium of donor tissues prior to transplantation to prevent/diminish acute tissue rejection. In contrast to highly specific blocking mechanisms (e.g., anti-CD4; proteolytic removal of RBC A/B antigens), the generation of globally camouflaged (i.e., stealth) cells may more effectively prevent the often complex and redundant events leading to immune recognition of foreign cells.

Abstract: Blood transfusions have the potential to improve graft survival, induce sensitization, and transmit infections. Current clinical practice is to minimize transfusions in renal transplantation candidates, but it is unclear if the evidence continues to support pre-transplant transfusion avoidance. Changes in the Medicare prospective payment system may increase transfusion rates. Thus there is a need to re-evaluate the literature to improve the management options for renal transplant candidates. A review applying a systematic approach and conducted using MEDLINE®, Embase®, and the Cochrane Library for English-language publications (timeframe: 01/1984–03/2011) captured 180 studies and data from publically available registries and assessed the impact of transfusions on allosensitization and graft survival, and the impact of allosensitization on graft survival and wait time. Blood transfusions continued to be a major cause of allosensitization, with allosensitization associated with increased rejection and graft loss, and longer wait times to transplantation. Although older studies showed a beneficial effect of transfusion on graft survival, this benefit has largely disappeared in the post-cyclosporine era due to improved graft outcomes with current practice. Recent data suggested that it may be the donor-specific antibody component of allosensitization that carried the risk to graft outcomes. Results of this review indicated that avoiding transfusions whenever possible is a sound management option that could prevent detrimental effects in patients awaiting kidney transplantation.

Abstract: Immunological recognition of foreign cells is a primary concern in both transfusion and transplantation medicine. Our unique approach to this problem is to globally camouflage the surface of the foreign cell using nonimmunogenic, long chain polymers such as methoxypoly(ethylene glycol) [mPEG]. mPEG-modification of red blood cells effectively attenuates both antibody binding to surface epitopes and decreases the inherent immunogenicity of foreign, even xenogeneic red cells. These cells exhibit normal structural and functional characteristicsin vitro and exhibit normal in vivo survival in animal models. Pegylation of white blood cells (particularly antigen presenting cells and T lymphocytes) surprisingly prevents recognition of foreign class II molecules and prevents T cell proliferation in response to foreign MHC molecules. Potential applications for the covalent binding of nonimmunogenic, long chain polymers (e.g., PEG) to intact cells include, but are not limited to: 1) derivatized RBC to diminish transfusion reactions arising from sensitization to minor blood group antigens (allosensitization) in the chronically transfused (e.g., sickle and thalassemia patients); 2) use of mPEG modification of "passenger" lymphocytes to prevent immune recognition and graft versus host disease; and 3) derivatization of the vascular endothelium of donor tissues prior to transplantation to prevent/diminish acute tissue rejection. In contrast to highly specific blocking mechanisms (e.g., anti-CD4; proteolytic removal of RBC A/B antigens), the generation of globally camouflaged (i.e., stealth) cells may more effectively prevent the often complex and redundant events leading to immune recognition of foreign cells.