HLA mismatches and PRA in kidney retransplants.

1. For kidney transplants, overall graft survival with 1st transplants was better than with multiple transplants. 2. One-year graft survival rates have become similar with 1st and 2nd transplants, but some differences persisted for 5-year survival. 3. HLA mismatches have decreased with both 1st and 2nd DDTs, but with 1st and 2nd LDTs HLA mismatches remained at almost the same level. 4. PRA levels increased with the number of transplants. 5. The percent of 1st transplant patients with 0% PRA has increased year by year. However, with 2nd transplants the percent with higher PRA levels also increased year by year. 6. The trend in number of HLA mismatches was similar with both 1st and 2nd DDTs and LDTs even when higher HLA mismatch levels increased over the years. 7. The graft survival of all PRA levels improved. The differences in 1-year graft survival between each PRA group became smaller, and pretransplant PRA diminished with 1-year graft survival. However, pretransplant PRA still affected 5-year graft survival.

Association of kidney transplant failure and antibodies against MICA.

Despite the progress in renal transplantation, acute rejection and graft failure still occur and chronic rejection continues to be the main problem in long-term allograft survival. Although kidney transplant rejection has been linked to anti-HLA antibodies, not all patients with failed kidney transplants have anti-HLA antibodies, indicating that other loci may be involved. Sera of 63 patients who experienced kidney rejection were compared against sera of 82 patients with functioning transplants. Sera were examined for IgG and IgM anti-HLA Class I and II antibodies. They were also tested by cytotoxicity against panels of 26 endothelial cell lines, 8 MHC class I chain-related gene A (MICA) recombinant cell lines, and 28 B lymphoblast cell lines. Among patients whose transplants failed, 65% had anti-HLA antibodies compared with 45% of those with functioning kidneys (p < 0.05). Similarly, among those whose transplants failed, 41% had anti-endothelial cell antibodies in contrast to 22% in functioning patients (p < 0.05). Among patients whose grafts failed, 52% had anti-MICA antibodies versus 21% of those with functioning grafts (p < 0.001). Eleven patients with failed grafts and 32 with functioning grafts were negative for all of the above. However, 6 of the former and 7 of the latter showed positive cytotoxicity against B lymphoblasts (p < 0.05). Taking all antibodies together, 92% of patients with graft failure had antibodies as opposed to 70% of patients with functioning grafts (p < 0.001). We postulate that antibodies against HLA, MICA, endothelial cells, and B lymphoblasts could be independently involved in the slow process of chronic graft failure.

Does MICA influence acute rejection in kidney transplantation?

MHC class 1-related chain A (MICA) has been reported to be recognized by specific antibodies in the sera of transplanted patients, and it may be a target molecule in allograft rejection. MICA was originally pointed out to be an HLA-related polymorphic gene, the product of which may be recognized by a subpopulation of intestinal gamma delta T-cells and may play a role in the activation of a subpopulation of natural killer cells. Although their association with chronic rejection has been demonstrated before, there are few reports of any relation with acute rejection. We encountered a possible case of MICA-related acute early rejection. The recipient was a 25-year-old female; the original disease was IgA nephropathy, and the hemodialysis period was 12 months. She underwent ABO-compatible living-related renal transplantation from her mother. The HLA type was A24, A31, B7, B52, DR1, and DR15 in the donor and A31, A33, B7, B44, DR1, and DR12 in the recipient. A pre-operative direct cross-match was negative by a conventional cytotoxic test, and HLA class 1 and 2 antibodies were negative by LABScreen single antigen testing. Induction immunosuppressive therapy was started with TAC, MMF, MP, and BXM. The graft functioned at once, and SCr was 2.4 mg/dl on post-transplant day 1. SCr increased from post-transplant day 2, and oliguria progressed. Hemodialysis was restarted on post-transplant day 6. A biopsy revealed Banff 2b vascular rejection. The graft was finally rescued by steroid pulse and plasma exchange therapy. SCr went down to 1.07 mg/dl, and a re-biopsy showed improvement on post-transplant day 42. HLA class 1 and 2 antibodies were negative during this period, and MICA019 antibody was higher before transplantation retrospectively. Additionally, this antibody titer was decreased at the time of discharge. These data show that MICA may induce rejection in the early phase of renal transplantation. Further study is needed to evaluate this phenomenon.

Serial ten-year follow-up of HLA and MICA antibody production prior to kidney graft failure.

The role of HLA antibodies in chronic allograft rejection was examined utilizing a unique resource of sera collected annually and stored over a 12-year period from patients with rejected or retained grafts. In patients selected for not having preformed HLA antibodies, 679 postoperative serial serum samples from 39 patients who rejected their grafts and 26 with functioning grafts were tested for HLA Class I and Class II antibodies by flow cytometry and for MICA antibodies by cytotoxicity on recombinant cell lines. HLA antibodies were found in 72% of patients who rejected grafts, compared to 46% with functioning transplants (p<0.05). In addition, the incidence of IgG HLA plus MICA antibodies was higher (77%) among those with failed transplants than those with functioning transplants (42%) (p<0.01). Finally, if patients with IgM anti-HLA antibodies were included, 95% of the 39 patients who rejected their grafts had HLA or MICA antibodies, compared to 58% with functioning grafts (p<0.01). Patients who rejected transplants had HLA and MICA antibodies more frequently than those with functioning grafts. These antibodies found in the peripheral circulation, were not necessarily donor-specific, but their association with failure is consistent with a causality hypothesis.

Cardiac myocytes are recruited by bone marrow-derived cells in intact murine heart.

It is generally believed that the cardiac myocytes withdraw from the cell cycle shortly after birth and thereafter any loss of myocardial tissue cannot be repaired. However, recent reports indicate that cardiac myocytes can be regenerated by stem cells derived from bone marrow in the damaged hearts. In this study, we investigated whether bone marrow-derived cells can differentiate into cardiac myocytes in the intact hearts. We performed bone marrow transplantation from syngenic male mice to female c57/B6 mice. In female mice's hearts, the presence of cells from male mice was examined by FISH method that detects Y chromosome. Using the same samples, we also performed immunohistochemical staining with muscle specific antibodies. In the heart sections of female mice, there were some cells that were considered as differentiated myocytes derived from male bone marrow (0.01~0.09% of total myocytes) and the proportion of the cells increased as the period after bone marrow transplantation became longer (3 months after vs. 8 months after). These results suggest that, not only in the damaged heart but also in the intact heart, a portion of cardiac myocytes is recruited by bone marrow-derived cells.