Extended major histocompatibility complex haplotypes, ancestry and acute kidney transplant rejection in Mexicans.

INTRODUCTION: Extended major histocompatibility complex (MHC) haplotypes are associated with several autoimmune diseases, and these appear to depend on ancestry. OBJECTIVE: To evaluate the association of extended MHC gene frequencies, ancestry, and acute rejection. MATERIAL AND METHODS: 127 living kidney transplant recipients who underwent kidney transplantation in Mexico City between January 2004 and October 2007 with follow up until October 2008. The primary outcome was biopsy proven acute rejection. Ancestry was considered as either Amerindian or admixtures with Caucasian, African or Oriental genes. Allele and haplotype frequencies were estimated for HLA A, B and DR loci. Hardy Weinberg (HW) and delta values were analyzed to test for linkage disequilibrium (LD). RESULTS: There were no significant differences in the baseline characteristics between groups. 50% were men, and 28, 61 and 10% of the patients shared zero, one or two haplotypes, respectively. The whole population was Hispanic and born in Mexico. Median PRA was 0%. Allelic variance in all MCH loci was in HW equilibrium, 14% developed acute rejection. There was a high frequency of Amerindian haplotypes; admixture genes and LD were higher in the group with acute rejection. When compared to the group without acute rejection, the haplotype A1*B8*DR3 was more frequent in donors in whom their recipients had acute rejection (p = 0.008), while A28*B39*DR4 was more common in the recipients with acute rejection (p = 0.003). Multivariate Cox regression models did not attenuate these associations. CONCLUSIONS: Ancestry and LD may be associated with risk of acute rejection and may therefore be useful in directing immunosuppression.

A non-allogeneic stimulus triggers the production of de novo HLA antibodies in healthy adults.

BACKGROUND: Transplant recipients develop antibodies against a wide array of HLA specificities, and not only against the antigens to which they have been exposed. The aim of the present study was to establish if HLA-unrelated immune stimulation is capable of triggering the production of HLA antibodies. METHODS: We determined the presence of HLA antibodies in 20 healthy adults before and after the administration of an immune stimulus (hepatitis B vaccine plus tuberculin skin test). HLA antibodies were assessed with a flow-cytometry based system. RESULTS: At baseline, HBsAg antibodies were detected in protective titers in 75% of the subjects; HLA antibodies were negative in all but one. One week after the antigenic stimulus, HBsAg antibody titers increased significantly, without any detectable changes in HLA antibodies. Surprisingly, HLA antibodies developed in 8 participants one month after the application of the stimulus. One additional subject developed HLA antibodies one month later. Therefore 9/20 subjects became PRA positive during the observation period. Antibody specificities were identified by single antigen assay. The alloantibody response elicited by the immune stimulus was not consistent with memory cell stimulation. CONCLUSIONS: The findings of this study demonstrate that a non-HLA antigenic stimulus is capable of eliciting the development of HLA antibodies in healthy adults.

HLA and MICA antibodies: further evidence of their impact on graft loss two years after their detection.

1. At the median post-transplant follow-up (to Ab evaluation) of 51.4 months, the prevalence of anti-HLA and anti-MICA Abs was 21.9% and 19%, respectively. 2. Overall, of the 196 patients included, 124 (63.3%) were negative to all tested Abs, and 72 (36.7%) were positive for: HLA Abs alone = 34; MICA Abs alone = 29; and HLA + MICAAbs = 9. 3. Two years after Ab evaluation, graft survival was significantly lower for patients with HLA + MICA Abs (p = 0.046). 4. The proportion of patients without CNI drugs at the time of Ab evaluation was greater in patients with one Ab and even greater in those with two Abs (HLA + MICA) when compared to patients with a negative Ab determination (p = 0.037).

[Husband to wife kidney transplantation in five multiparous women: sensitization or tolerance after pregnancy?]. / Trasplante renal de esposo a esposa en cinco mujeres multíparas. Efecto sensibilizante o efecto "tolerogénico" de la gestación?

BACKGROUND: Pregnancy is a known cause of immunological sensitization and it has been reported graft survival to be lower in husband to wife kidney transplantation if the wife had been pregnant (mutual children) as compare to those cases without pregnancies. Previous exposure to husband HLA antigens during pregnancies may lead to specific sensitization to subsequent allografts. AIM: To communicate the fate of kidney allograft in husband to wife transplantation when the recipient had been pregnant. PATIENTS AND METHODS: From 682 renal transplants performed at INCMNSZ 5 corresponded to husband to wife transplants. All the recipients were multiparous and had received multiple blood transfusions. Pretransplantation lymphocytotoxic cross-match testing were performed by complement dependent citotoxicity with antihuman globulin added (AHG-CDC), being negative in all cases for T and B cells. All the patients received triple-drug immunosuppressive therapy, additionally, anti-IL2R monoclonal antibodies were used in two cases. RESULTS: Two patients developed: accelerated acute rejection (case 1), and acute humoral rejection (case 5), respectively. Graft in these patients were loss to rejection and transplant nephrectomy accomplished. The remaining three patients (cases 2, 3, and 4) has not had any rejection episode, and have had excellent graft outcome at 34, 30, and 21 months posttransplant, respectively. CONCLUSIONS: Why under similar conditions some husband to wife kidney transplant recipients developed an adverse humoral immunological events while others maintain excellent long-term graft outcome? Is it possible to speculate that for some women pregnancy is in fact a sensitizing event, while in others it promotes "immunological acceptance"? At present there is no a test that characterized one and other group. Even though pretransplantation cross-match testing by flow cytometry is more sensitive than AHG-CDC, its negative result is by no means an absolute guarantee that an adverse anamnestic immunological event will not occur.

In vivo IL-10 and TGF-beta production by PBMC from long-term kidney transplant recipients with excellent graft function: a possible feedback mechanism participating in immunological stability.

BACKGROUND: Interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta) are Th2-derived multifunctional cytokines that exhibit potent immunoregulatory and anti-inflammatory properties which might prolong graft survival. The aim of this study was to explore whether spontaneous production of IL-10 and TGF-beta by blood mononuclear cells correlates with excellent long-term graft function. METHODS: A cross-sectional study was carried out in 32 kidney transplant recipients, without albuminuria, treated with azathioprine and prednisone. Spontaneous IL-10 and TGF-beta were measured by enzyme-linked immunosorbent assay in supernatants from 24 h cultured unstimulated peripheral blood mononuclear cells. Both cytokines were also determined in 10 healthy kidney donors. RESULTS: There was no correlation between IL-10 or TGF-beta with any variable tested, namely age, SCr, histocompatibility, and post-transplant follow-up. In vivo IL-10 production displayed a statistical trend to be higher in transplant recipients than in controls (362.3 +/- 465, range 12.5-1929.3 pg/ml, and 189 +/- 170, range 4.17-485.7 pg/ml, respectively; p = 0.08), whereas no difference was observed in TGF-beta among the same groups (134.7 +/- 79.2, range 68-421 pg/ml, and 121.4 +/- 25.8, range 75-151 pg/ml, respectively). Interestingly, a statistically significant inverse correlation was observed between IL-10 and TGF-beta in kidney transplant recipients (p = 0.03). CONCLUSIONS: The higher IL-10 production observed in long-term kidney transplant recipients supports the notion that this cytokine contributes in decreasing allogenic immune responses and allows prolongation of allograft survival. The balance between TGF-beta and IL-10 may be of paramount importance in graft acceptance.

Frequencies of HLA-A and HLA-B alleles in a Mexico City mestizo sample.

The aim of the present study was to evaluate the frequency of HLA-A and HLA-B antigens in a sample of the Mexico City Mestizo population. Previous similar studies were done by other authors in nonrelated individuals, while the present investigation was performed in families (parents and offspring), and therefore, a more accurate estimate of gene and haplotype frequencies was obtained. The predominant antigens in descending order are A2, A24, and A28 at the A locus, whereas B39 and B35 are at the B locus, all with gene frequencies above 0.1. As expected, the two more frequent haplotypes were A2-B16 and A2-B35 (considering main specificities), both with frequencies of 0.056. Seven of the 18 significant delta values of the haplotypes (observed vs. expected) remained significant after correcting for the number of comparisons, indicating the presence of linkage disequilibrium between the HLA-A and HLA-B regions. However, only A1-B8 and A19-B13 were found to be in disequilibrium in another Mexico City Mestizo sample which had very similar HLA-A and HLA-B allele frequencies to those in the present survey, suggesting that the biological significance of the other associations is rather doubtful. Am. J. Hum. Biol. 9:1-5 © 1997 Wiley-Liss, Inc.