RESUMEN
BACKGROUND: Islet cell transplantation can cure type 1 diabetes (T1D), but only a minority of recipients remains insulin-independent in the following years. We tested the hypothesis that allograft rejection and recurrent autoimmunity contribute to this progressive loss of islet allograft function. METHODOLOGY/PRINCIPAL FINDINGS: Twenty-one T1D patients received cultured islet cell grafts prepared from multiple donors and transplanted under anti-thymocyte globulin (ATG) induction and tacrolimus plus mycophenolate mofetil (MMF) maintenance immunosuppression. Immunity against auto- and alloantigens was measured before and during one year after transplantation. Cellular auto- and alloreactivity was assessed by lymphocyte stimulation tests against autoantigens and cytotoxic T lymphocyte precursor assays, respectively. Humoral reactivity was measured by auto- and alloantibodies. Clinical outcome parameters--including time until insulin independence, insulin independence at one year, and C-peptide levels over one year--remained blinded until their correlation with immunological parameters. All patients showed significant improvement of metabolic control and 13 out of 21 became insulin-independent. Multivariate analyses showed that presence of cellular autoimmunity before and after transplantation is associated with delayed insulin-independence (p = 0.001 and p = 0.01, respectively) and lower circulating C-peptide levels during the first year after transplantation (p = 0.002 and p = 0.02, respectively). Seven out of eight patients without pre-existent T-cell autoreactivity became insulin-independent, versus none of the four patients reactive to both islet autoantigens GAD and IA-2 before transplantation. Autoantibody levels and cellular alloreactivity had no significant association with outcome. CONCLUSIONS/SIGNIFICANCE: In this cohort study, cellular islet-specific autoimmunity associates with clinical outcome of islet cell transplantation under ATG-tacrolimus-MMF immunosuppression. Tailored immunotherapy targeting cellular islet autoreactivity may be required. Monitoring cellular immune reactivity can be useful to identify factors influencing graft survival and to assess efficacy of immunosuppression. TRIAL REGISTRATION: Clinicaltrials.gov NCT00623610.
Asunto(s)
Autoinmunidad , Trasplante de Islotes Pancreáticos , Islotes Pancreáticos/inmunología , Autoanticuerpos/inmunología , Humanos , Linfocitos T Citotóxicos/inmunología , Resultado del TratamientoRESUMEN
BACKGROUND: Preexisting alloantibodies against the mismatched HLA class I antigens of the donor, when present in current sera, are believed to be detrimental for kidney graft survival. The relevance of a positive crossmatch with historical sera only is still a matter of debate. Previous studies showed a correlation between the presence of alloantibodies and the presence of alloactivated cytotoxic T lymphocytes (CTLs). We wondered whether the persistence of activated CTLs might explain the poor results in a proportion of patients with a historical positive crossmatch. METHODS: We tested 10 sensitized patients to determine whether activated CTLs persist when the antibodies disappear. Limiting dilution assays were performed in the presence and absence of cyclosporine (CsA) to distinguish between activated (primed) (CsA resistant) and naive (CsA sensitive) CTLs. To test the clinical relevance of the persisting CTLs, eight sensitized patients, who underwent a kidney transplantation across a positive historical crossmatch, were retrospectively tested for the presence or absence of activated donor-specific CTLs at the day of transplantation. RESULTS: In the first group, four patients had CsA-sensitive CTLs, three patients had CsA-resistant CTLs, and three other patients had CsA-sensitive CTLs for a particular HLA antigen and CsA-resistant CTLs for another HLA antigen. In the transplant group, four patients with CsA-sensitive CTLs at the day of transplantation were found to have a good graft function. In the other four patients, the presence of CsA-resistant donor-specific CTLs was associated with rejection and early graft loss. CONCLUSION: The present study suggests that determining the activation state of CTLs specific for the HLA mismatch against which antibodies were present in historical sera, may be relevant to transplant outcome in patients who undergo transplantation across a positive historical crossmatch.
Asunto(s)
Rechazo de Injerto/inmunología , Antígenos de Histocompatibilidad Clase I/análisis , Trasplante de Riñón/inmunología , Linfocitos T Citotóxicos/química , Linfocitos T Citotóxicos/inmunología , Linfocitos B/inmunología , Rechazo de Injerto/diagnóstico , Prueba de Histocompatibilidad , Humanos , Isoanticuerpos/inmunología , Isoantígenos/inmunología , Fallo Renal Crónico/inmunología , Fallo Renal Crónico/cirugía , Valor Predictivo de las Pruebas , Resultado del TratamientoRESUMEN
BACKGROUND: The presence of donor-specific HLA antibodies is generally considered to be a contraindication for transplantation, even when these antibodies are only present in historical sera. Previous studies showed that donor-specific antibodies in current sera were associated with the presence of primed cytotoxic T cells (CTLs) with a high avidity for donor HLA class I antigens. The presence of these CTLs is considered to be a reflection of an activated immune system and a contraindication for transplantation with a donor sharing these particular HLA antigens. METHODS: In the present study we compared the incidence of primed CTLs in patients with anti-HLA antibodies in current sera and in patients with anti-HLA antibodies in historical sera only. Cytotoxic T lymphocyte precursor (CTLp) frequencies and the incidence of primed CTLs directed against HLA class I antigens to which the patient had formed antibodies were studied in 37 sensitized renal patients. As controls, antigens to which a patient has never formed antibodies were tested. RESULTS: In patients with antibodies in current sera mainly primed CTLs were detected, whereas in patients where the antibodies had disappeared mainly naive CTLs were detected. However, in four patients primed CTLs persisted despite the fact that the HLA antibodies had disappeared. CONCLUSION: Considering the previously described association between primed CTLs and graft rejection, these findings may be relevant for the selection of patients who can be transplanted across a positive historical crossmatch. If the antibodies have disappeared and only naive CTLs are present, a successful transplantation should be feasible. A prospective study will reveal whether this is indeed the case.