Posttransplant major histocompatibility complex class I chain-related gene A antibodies and long-term graft outcomes in a multicenter cohort of 779 kidney transplant recipients.

BACKGROUND: The impact of major histocompatibility class I chain-related A (MICA) antibodies on renal graft outcomes is unclear. The goal of this work was to assess the impact of posttransplant MICA antibodies, assayed at 1 year, with two commercially available kits, on long-term renal graft outcomes. METHODS: We retrospectively tested sera from 779 kidney transplant recipients with two single-antigen flow bead assays 1 year after transplantation. Samples were considered positive for MICA if they were positive in both tests or positive for MICA specificities that were present in one kit only. The main outcome was 4-year death-censored graft survival. RESULTS: The prevalence of MICA antibodies was 5.4% at 1 year. MICA+ patients were more frequently human leukocyte antigen (HLA) sensitized and regrafted. Four-year death-censored graft survival was not different between MICA+ and MICA- patients (97% vs. 94%, P=0.28). By Cox multivariate analysis, independent risk factors for graft loss were as follows: number of HLA DR mismatches, acute rejection within the first year posttransplantation, 1-year serum creatinine, and the presence of HLA antibodies at 1 year, but not the presence of MICA antibodies. CONCLUSIONS: These data do not support an independent pathogenic role for MICA in long-term renal graft injury and question the interest of posttransplant monitoring of MICA antibodies with single-antigen flow bead assays currently available.

Computer-aided human leukocyte antigen association studies: a case study for psoriasis and severe alopecia areata.

We present an integer programming model for human leukocyte antigen (HLA) association studies based on the parsimony criterion. The model is simple, compact, easy to implement, and able to handle datasets containing up to 200 phenotypes. Computational experiments carried out on patients affected by psoriasis and severe alopecia areata show that the model is consistent with the experimental haplotype frequencies, showing, for the considered diseases at least, a high reliability of the predictions. These promising results provide perspective on computer-aided association studies and encourage the development of efficient exact computational approaches for haplotype estimation.

Major histocompatibility complex class 1 chain-related antigen a antibodies: sensitizing events and impact on renal graft outcomes.

BACKGROUND: Major histocompatibility complex class 1 chain-related antigen A (MICA) antibodies (Abs) have been associated with renal graft loss in one large cohort. The triggering factors for MICA Abs and their autologous or allogeneic specificity have not been well defined. More data on the impact of MICA on renal grafts outcome are needed. METHODS: We tested sera from 494 controls and 597 patients with chronic kidney disease (CKD) for MICA using Luminex. Forty CKD MICA+ patients were genotyped for MICA alleles to determine their auto- or allospecificity. We compared MICA+ with MICA- renal transplant recipients with regard to acute rejection episodes and long-term survival. RESULTS: Blood transfusions, previous transplantation, and more than two pregnancies were independent risk factors for the presence of MICA Abs, as were CKD stage V status and male gender. Among the 40 genotyped patients, allo-Abs alone were present in 32 patients, both auto- and allo-Abs in 4 patients, and auto-Abs alone in 4 patients. When we compared MICA+ with MICA- patients, the incidence of acute rejection episodes during the first year (10.2% vs. 12.8%), as well as 1-year creatinine and proteinuria, were similar in both groups. At 10 years, actuarial patient (97.8% vs. 87.6%) and overall graft survival (76% vs. 72%) were similar between MICA+ and MICA- patients. CONCLUSIONS: In summary, (1) sensitizing events for MICA Abs are the same as for human leukocyte antigen Abs; (2) MICA Abs did not adversely affect renal graft outcomes in our cohort.

Early immunosuppression withdrawal after living donor liver transplantation and donor stem cell infusion.

Long-term results of organ transplantation are still limited by serious side effects of immunosuppressive drugs. A major issue, therefore, is to elaborate novel therapeutic protocols allowing withdrawal or minimization of immunosuppressive therapy after transplantation. We report on 3 patients prospectively enrolled in an original protocol designed to promote graft acceptance in living donor liver transplantation, using posttransplant conditioning with high doses of antithymocyte globulin followed by injection of donor-derived stem cells. In 2 patients, early immunosuppression withdrawal was possible, without subsequent graft deterioration. In these 2 cases, in vitro studies showed indices of immunological tolerance as assessed by specific hyporesponsiveness to donor alloantigens in mixed lymphocytes culture. In the third patient, acute rejection rapidly occurred after discontinuation of immunosuppression, and minimal immunosuppression has to be maintained during long-term follow-up. In this case, a clearly distinct immunoreactive profile was observed as compared to tolerant patients, as no specific modulation of the antidonor response was observed in vitro. Of note, no macrochimerism could be detected in any of the 3 patients during the follow-up. In conclusion, these clinical observations demonstrated that, despite the absence of macrochimerism, donor stem cells infusion combined with recipient conditioning may allow early immunosuppression withdrawal or minimization after liver transplantation.

A rapid test to monitor alloreactive responses in whole blood using real-time polymerase chain reaction.

Rapid, simple, and reliable assays to monitor allogeneic responses are essential for the safe development of novel protocols of tailored immunosuppression. Herein, we describe a real-time polymerase chain reaction method based on interleukin-2 and interferon-gamma mRNA quantification upon stimulation of whole blood with allogeneic T cell-depleted peripheral blood mononuclear cells. The technique requires only small blood volumes and results can be obtained within 48 hours. Data obtained in a liver transplant patient receiving a tolerance induction protocol based on the infusion of donor-type hematopoietic stem cells suggest that this rapid whole blood mixed lymphocyte reaction assay could be valuable for the monitoring of patients undergoing solid organ or hematopoietic stem cell transplantation.

Association between the TNF-2 allele and a better survival in cardiogenic shock.

STUDY OBJECTIVES: Tumor necrosis factor (TNF)-alpha has been implicated in the pathophysiology of heart failure. We explored a possible association between TNF-alpha, interleukin (IL)-6, IL-10, transforming growth factor (TGF)-beta, and interferon (IFN)-gamma cytokine polymorphisms, their in vivo production, and mortality from cardiogenic shock. DESIGN: Prospective, observational study. SETTING: Thirty-one bed, university, medicosurgical department of intensive care. PATIENTS: Thirty-three adult patients with cardiogenic shock of recent (< 4 h) onset. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: TNF-alpha, IL-6, IL-10, TGF-beta1, and IFN-gamma plasma levels were measured by enzyme-linked immunosorbent assay. Polymorphisms of TNF-alpha within the promoter at position -308a-->g, IL-6 within the promoter at position -174c-->g, IL-10 within the promoter at position -1082a-->g/-819t-->c and -819t-->c/-592a-->c, TGF-beta1 at codon 10t-->c and codon 25c-->g, and IFN-gamma at intron 1 at position + 874t-->a were studied. The 33 patients had a mean (+/- SD) age of 64 +/- 17 years and a mean simplified acute physiology score II of 62.3 +/- 15.3. Twenty-three patients (70%) died in the ICU, including 21 of 26 patients (81%) in the TNF-1 group but only 2 of 7 patients (29%) in the TNF-2 group (p = 0.016). There were no significant differences in median plasma TNF-alpha levels between the TNF-1 and the TNF-2 groups, but TGF-beta1 levels were higher in the survivors than in the nonsurvivors (median, 866 pg/mL; range, 384 to 1,966 pg/mL; vs median, 454 pg/mL; range, 167 to 1,266 pg/mL, respectively; p = 0.02). There were no significant differences in TNF-2 polymorphism between the patients with cardiogenic shock and a group of healthy control subjects (7 of 33 patients vs 13 of 48 subjects, respectively; p = 0.61), but IFN-gamma polymorphism was less common in the cardiogenic shock group (p = 0.034). CONCLUSIONS: Patients with the TNF-2 allele have no greater risk of cardiogenic shock but a better survival rate when it develops. Different genetic factors appear to influence the risk of development of, and outcome from, cardiogenic shock.