Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Beyond ABO and human histocompatibility antigen: other histocompatibility antigens with a role in transplantation Suchitra Sumitran-Holgersson Introduction Human histocompatibility antigens (HLAs) are highly polymorphic cell-surface-expressed molecules with more than 1600 different alleles presently documented in humans [1]. This property increases the chances of sen- sitization (development of cellular and humoral responses) through exposure to nonself-major histocompatibility complex (MHC) or other nonself-antigens – commonly through blood transfusions, pregnancies or previous trans- plantation. Activated graft endothelium express HLA class I and class II antigens, so it may be the target of preformed HLA antibodies (Abs) [2]. The presence of donor lymphocyte-reactive HLA-specific Abs either before and/or after organ allograft transplantation is well established [3  ]. A number of other clinically relevant non-HLA antigenic determinants are expressed on endo- thelial cells as well, however, and hyperacute and acute rejections [4–9] may occur in the absence of detectable HLA Abs, suggesting that non-HLA antigenic systems may also play a role in organ allograft. Despite negative lymphocyte crossmatches, which help detect HLA anti- bodies, approximately 20–30% of kidneys are lost within 1-year posttransplant. The most ubiquitous antigens to which the population is sensitized are the ABO blood group antigens [10,11]. Based on population frequencies in the United States, the chance that any two individuals will be ABO incompatible is 35%. The non-HLA blood group antigens, therefore, are also potential targets of humoral alloimmune response and the clinical importance of these antibodies with organ graft outcome is well recognized [12]. Terasaki [13] (a meticulously performed study demon- strating the degree to which HLA, non-HLA and non- immunological factors play a role in organ graft loss) reported that 38% of graft failures are due to non-HLA, 18% due to HLA and 43% are due to nonimmunological Division of Transplantation Surgery, Karolinska University Hospital-Huddinge, Stockholm, Sweden Correspondence to Dr Suchitra Sumitran-Holgersson, Department of Transplantation Surgery B56, Karolinska University Hospital-Huddinge, S-141 86 Stockholm, Sweden Tel: +46 8 58583988; fax: +46 8 58581390; e-mail: suchitra.holgersson@karolinska.se Current Opinion in Organ Transplantation 2008, 13:425–429 Purpose of review In the past few years, there has been an increasing interest in nonhuman histocompatibility antigens as targets of injury in organ-transplant recipients. This increased interest has been spurred by the fact that human-histocompatibility-antigen- identical kidney transplants also undergo immunological rejections. Recent findings Polymorphisms within nonhuman histocompatibility antigen genes associated with evoking an immune response to alloantigens are currently being studied for their association with transplant outcome. Studies identify the polymorphic major histocompatibility complex class I-related chain A as one of the important nonhuman histocompatibility antigen antibody targets in kidney allograft rejections. Use of endothelial cells as targets may clarify the specificities of other clinically relevant nonhuman histocompatibility antigen antibodies in graft rejections. Summary This review summarizes current knowledge of the specificities and associations of nonhuman histocompatibility antigens with graft outcome after transplantation. The aims of current research into the role of nonhuman histocompatibility antigens and their genetics in predicting outcome are to develop an improved insight into the basic science of transplantation and to develop a risk or prognostic index for use in the clinical setting. Undoubtedly, this will continue to be an area of interest in terms of fully understanding the role of nonhuman histocompatibility antigens as targets of immune- mediated injury and the potential for clinical intervention. Keywords antibodies, human histocompatibility antigen, major histocompatibility complex class I-related chain A, nonhuman histocompatibility antigens, transplantation Curr Opin Organ Transplant 13:425–429 ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins 1087-2418 1087-2418 ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins