Use of current SPIs for definition of HLA-specific antibodies, coupled with a molecularly based algorithm for determination of acceptable antigen mismatches has added to the potential application of acceptable mismatch programs (107, 108). the patient sensitized to HLA and, if so, what are the strengths of the patients antibodies? This information can then be used to define the HLA type of an immunologically optimal donor and the probability of such a donor occurring. A probability that is considered to be too low may require expanding the donor populace through paired donation or modifying what is acceptable, which may require employing treatment to overcome immunologic barriers such as increased immunosuppression or desensitization. Thus, transplantation must strike a balance between the risk associated with waiting for the optimal donor and the risk associated with a less than optimal donor. Keywords: HLA matches, HLA mismatches, immunogenicity, match probability, sensitization, repeated mismatches, donor-specific antibody Introduction There is overwhelming evidence of the benefits of HLA matching in organ transplantation including better graft function, longer graft Avicularin and patient survival, and reduced risk of sensitization. However, when a well-matched related donor is not available, the wait for a well-matched unrelated donor can be prolonged, which can reduce quality of life, impede physical and cognitive development in the young, and increase the risk of death. Furthermore, in countries where there is usually substantial ethnic diversity, allocation of Avicularin deceased donor organs by HLA match can result in a disparity, among ethnic groups, in access to transplantation. The effects of HLA matching are confounded by many factors that can affect outcome such as sensitization, immunosuppression, recipient ethnicity and age, and donor type and quality. Thus, transplantation is usually a balancing act between capturing the benefits of a well-matched transplant and diminishing the problems associated with achieving that transplant. Strategies must consider both the benefits and disadvantages of matching, the detrimental effects of mismatching, and what can be done to minimize negative effects of both matching and mismatching. Here, we will review the impact of HLA matching/mismatching on graft outcomes, other factors that impact the effect of HLA, other consequences of mismatches, and the factors that should be evaluated C HLA antigens, epitopes, and amino acids. We will examine the effect of HLA mismatches on the current transplant and on future transplants as well as HLA matching strategies for the non-sensitized and sensitized patients. Effect of HLA Matching/Mismatching on Outcomes Assessment of the effects of mismatching has been KIR2DL5B antibody confounded by variability over time of the ability to determine HLA phenotype accurately; by considering only matched but not mismatched antigens; by evaluating the effect of only Avicularin some HLA loci; and by the diminished sensitivity and specificity of cell-based assessments for HLA antibody. Although numerous early studies reported that increased numbers of matched antigens or decreased numbers of mismatched antigens led to improved graft and patient survival, improved graft function, and fewer rejection episodes, later reports suggested that ongoing improvements in immunosuppression therapies either diminished or eliminated any benefit of matching. However, large studies and more recent reports have reaffirmed the benefits to be derived from matching. Data from the Collaborative Transplant Study showed that with or without cyclosporine use, the renal transplant success rate was 20% higher when there was no mismatch of HLA-B and -DR than when there was a mismatch (1). Similarly, data from the United Network for Organ Sharing showed that long-term graft survival of deceased donor renal transplants with no HLA-A, -B, and -DR mismatch was nearly 20% better than for Avicularin fully mismatched grafts with a stepwise reduction in survival with each increased degree Avicularin of mismatch (2). Comparable results were observed in a study of more than 150,000 renal transplants in which 10-12 months graft survival of first deceased donor kidney transplants was 17% higher among the zero HLA-A, -B, and -DR-mismatched patients than among those fully mismatched with an even greater benefit derived in sensitized patients (PRA >50%) (3). When graft survival was examined for deceased donor renal transplants occurring in different eras, it was seen that 5-12 months graft survival was 11% higher among transplants occurring between 1995 and 2004 compared to those occurring.