Specific immune tolerance related to disparity in MHC class I region.

A specific immune tolerance in mature, immunologically competent individuals may be induced by incompatibility for some of the class I major histocompatibility complex (MHC) antigens. This is suggested by results of experimental and clinical studies of organ transplantation and of antibody production. These results indicate the existence of tolerance-promoting allogenic markers within the MHC class I region.

HLA-A incompatibility associated with enhanced long-term renal graft survival in HLA-B, DR mismatched transplants.

The effect of HLA-A matching on long-term cadaver kidney graft survival was analysed, on average, 6 years after transplantation in a total of 1085 cyclosporine (CyA)-treated patients. A beneficial effect of HLA-A mismatching on graft survival was found by univariate and multivariate analyses (P < 0.05). Enhanced graft survival was associated with HLA-A mismatching in transplants mismatched for HLA-B,DR (P = 0.03), but not in HLA-B,DR compatible transplants. High 6 year graft survival rates, 78% and 66%, were found in transplants mismatched for two or one HLA-A antigens, respectively, among patients without any acute rejection episode. This was significantly higher than the survival rate of 55% found in HLA-A compatible transplants (P = 0.001). In patients who had suffered from acute rejection episodes, a prolonged graft survival was also associated with HLA-A mismatching in HLA-B,DR mismatched transplants (P = 0.04). The beneficial effect on graft survival of HLA-A mismatching was most pronounced in patients treated with high/medium dose CyA and prednisolone (P = 0.004 overall and P = 0.0007 for HLA-B,DR mismatched transplants). In conclusion, HLA-A mismatching was associated with enhanced long-term renal graft survival in CyA-treated recipients of HLA-B,DR mismatched transplants. In clinical situations, the present results might, if confirmed, contribute to the prolongation of long-term graft survival. The results might indicate the existence of tolerance promoting allogeneic markers within the HLA-A class I region.

HLA-A region in highly sensitized patients: another immune response gene region.

HLA haplotypes were assigned by family typing in 94 prospective kidney transplant recipients. An HLA-A region of the HLA-A, B, DR haplotypes was found in association with high levels of antibodies against lymphocytes. There was a significant difference in the frequency of HLA-B8-positive haplotypes among the patients with regard to the distribution of HLA-A alleles (p = 0.0028); on the same haplotype the A1 and B8 alleles were found in moderately and weakly sensitized patients and HLA-A alleles other than A1 were present with B8 in highly sensitized patients. A significantly higher number of highly sensitized patients when compared with moderately sensitized patients had haplotypes with HLA-A alleles in negative linkage disequilibrium with HLA-B alleles (77 vs. 10%, p = 0.014). The results are in good agreement with a previous suggestion that the interaction between the HLA-A class I and class II regions regulates the immune response. Determination of HLA haplotypes might identify patients at high risk for broad and persisting sensitization.

C4 polymorphism and major histocompatibility complex haplotypes in IgA deficiency: association with C4A null haplotypes.

IgA-deficient individuals (n = 110) and six families comprising 9 cases of IgA deficiency were typed for HLA-A, -B, -DR, C4 and factor B. Phenotype frequencies were increased for HLA-B8 (p = 0.004), HLA-DR3 (p = 0.001) and homozygous C4AQ0 (p = 0.01) and decreased for HLA-B7 (p = 0.004), HLA-DR2 (p = 0.0001) and C4A3 (p = 0.00007) compared to controls. Homozygous C4A deficiency was found in 20% of IgA-deficient persons. As clearly suggested by investigation of families, the findings could be attributed to high prevalence of the extended major histocompatibility complex (MHC) haplotype [HLA-A1, B8, C4AQ0, C4B1, BfS, DR3] in IgA deficiency. All but 1 of the 9 IgA-deficient persons included in the family study carried this haplotype and 4 of them were homozygous. In the families, 3 persons with normal serum IgA concentrations had the same MHC haplotypes as their IgA-deficient relatives. The findings were also consistent with possible overrepresentation of other MHC haplotypes with aberrant C4 gene organization in IgA deficiency. As previously suggested, the presence of two MHC haplotypes associated with IgA deficiency appears to be a necessary but not sufficient requirement for manifestation of the condition. The putative existence of a recessive gene in the MHC with regulatory function with regard to IgA gene expression is consistent with the findings.

Blood transfusion in renal transplantation--the induction of tolerance by incompatibility for class I antigen.

Blood transfusion given before renal transplantation has been shown to have a powerful immune modulating effect on recipient response to kidney allograft. The mechanism responsible for this effect is still unknown. Here it is assumed that, due to incompatibility for HLA-A related class I antigens between blood donor and recipient, pretransplant blood transfusion may allospecifically induce in the recipient the generation of T cells that have a suppressive effect on T lymphocyte response to incompatible HLA class II antigens present on kidney allograft. Although in many respects this interpretation is still speculative, it is in accord with findings reported from clinical and experimental studies of the effect on graft survival of blood transfusion, both random and donor specific.

Adverse effect of blood transfusion on the long-term outcome of kidney transplantation.

In 116 patients treated with azathioprine and prednisolone, 2-year patient survival and primary renal allograft survival was analyzed with regard to the effects of pretransplant blood transfusion and of matching for HLA-A, HLA-B, and HLA-DR. Two years after transplantation, patient survival was significantly lower in transfused patients than in non-transfused patients (81 vs. 97%, p less than 0.05). A detrimental effect of blood transfusion on graft survival was found in conjunction with HLA-A compatibility (p = 0.01 overall, and p = 0.003 for HLA-B mismatched transplants). Among transfused patients, enhanced graft survival was associated with incompatibility for HLA-A (p = 0.02 overall, and p = 0.008 for HLA-B mismatched transplants), and with compatibility for HLA-B (p = 0.0006 overall, and p = 0.005 for HLA-A mismatched transplants). The present results indicate that blood transfusion may have detrimental effect on patient survival.

HLA-A antigen incompatibility and HLA-B antigen compatibility associated with enhanced kidney allograft survival in blood-transfused patients.

The combined effect on 2-year primary kidney allograft survival of pretransplant blood transfusion, HLA-DR matching, HLA-A matching, HLA-B matching and other factors was analyzed in 116 azathioprine- and prednisolone-treated patients. The results show an hitherto unreported, statistically significant association between incompatibility for HLA-A antigens and enhanced graft survival in transfused recipients of transplants mismatched for HLA-DR (p = 0.005) and for HLA-B (p = 0.008). As expected, compatibility for HLA-B antigens was significantly associated with increased graft survival in transfused recipients of both HLA-DR compatible (p = 0.004) and HLA-DR incompatible (p = 0.01) grafts. If confirmed, the findings foreshadow new aspects of HLA matching in kidney transplantation and might explain the beneficial effect of blood transfusion on renal allograft survival.

Human alloantiserum against PHA-activated cells. Cytotoxicity associated with the HLA-A3 antigen.

Sera from transfused patients frequently show reactivity against polymorphic determinants expressed on PHA-activated but not resting mononuclear cells. One of these sera shows cytotoxicity associated with the HLA-A3 antigen.