HLA-DR3 associated with improved kidney transplant survival.
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By using a Fab2 fragment blocking assay with cultured human B lymphoid cells and peripheral lymphocytes as targets, cytotoxic antibodies to la-like antigens, to HLA-A,B,C antigens, and to lymphocyte structures other than these two types of histocompatibility antigens were identified in serial post-transplant sera from 18 renal allograft recipients. Multiple combinations of these three types of antibodies were seen in 78% of the sera. A higher reactivity as well as higher titers of antibodies were found in patients with graft failure from rejection. The occurrence of anti HLA-A,B,C or anti la-like antibodies did not show any relationship to graft outcome. However, cytotoxic antibodies to other antigens (referred to as non-HLA antibodies) were detected in five of the six patients with graft failure and in only one patient with graft survival. In this latter patient, non-HLA antibodies occurred with a chronic rejection episode and were no longer detectable when the rejection ceased. This study shows that the Fab2 fragment blocking assay is a useful method to identify antibodies to multiple specificities in sera from kidney graft recipients, and suggests that non-HLA cytotoxic antibodies may be associated with graft rejection.
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The human immune system is very efficient at distinguishing between “ self” and “ non-self” antigens that are presented by major histocompatibility complex (MHC) cell surface proteins. The MHC molecules are continually monitored by lymphocytes to ensure that the correct self-antigens are presented ; the presence of any non-self antigens triggers an immune response. Donor specific human leukocyte antigen (HLA) antibodies can be detected in individuals who have been immunized as a result of blood transfusion, pregnancies or failed transplants. Antibodies directed to paternal HLA mismatches are found in 15-30% of women who have been pregnant. The alloimmunization against rare HLA antigens (rare HLA antigen – gene frequency <3% in general population) is of special interest because of great importance for donor selection in clinical transplantation. For this analysis we tested 123 sera from 103 women who had produced antibodies against the paternal HLA class I antigens. The sera were selectively chosen taking into account the possible presence of antibodies against rare paternal HLA antigens (anti-HLA-B53, -B56, -B55, -B70, -B49, -B63, -A23, -A2403). The sera were tested in a serologic crossmatch against the lymphocytes of the father and in a screening against a panel of 62 HLA typed individuals. The specificity of the anti-HLA antibodies was detected using the standard complement dependent microlymphocytotoxicity test (MLCT). The HLA phenotype of all women was determined using MLCT. Their husbands were typed using PCR-SSP DNA class I typing. Among 123 sera tested, 69 (56.1%) contained monospecific HLA antibodies (coefficient of correlation = 1) while for the rest of the sera coefficient of correlation was in the range of 0.5-0.9 (43.9%). Further analyses revealed that monospecific sera was always produced when the allosensizitation is due to HLA-B41 antigen, while on the other hand the allosensizitation to B51 antigen mostly results in bi- or oligo-specific sera. The alloimmunization against rare HLA antigens (B41, B50, B52, B60, B63) was detected in 8 women and was in concordance with the fathers’ HLA phenotype. This study of HLA antibody profiles after the pregnancy can be beneficial for the screening analysis of highly sensitized patients on the waiting list for kidney transplantation.
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In order to study the correlation between HLA mismatches and the cytotoxic T lymphocyte precursor frequency, we used a limiting dilution analysis to determine the CTLp frequencies against individual mismatched HLA-A and -B alloantigens in 21 patients waiting for a renal transplant. Altogether, thirty-three mismatched HLA-A antigens and 55 HLA-B antigens were tested. The CTLp frequencies against mismatches of HLA-B locus antigens were found to be significantly higher than those against HLA-A antigens (P <0.002). This may explain why matching for HLA-B antigens is more important for a good renal allograft survival than matching for HLA-A antigens.
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