RESUMEN
End-stage renal disease (ESRD) patients with high levels of anti-HLA panel reactive antibodies (PRA) represent an increasing group in which sensitization, induced by pregnancies, previous transplants, and blood transfusions, considerably delay the opportunity to receive a graft. Currently, more than 50% of the 4700 patients awaiting transplantation in France are sensitized, of which 33% are defined as hyperimmunized (PRA greater than = 80%), and only 9.5% of the total number of transplants have been done in highly sensitized recipients. The magnitude of this problem, similar in Europe and North America, explains why more active strategies for managing hyperimmunized patients have been introduced during the past decade. Clearly, the simplest is finding of a well-matched organ that does not carry the HLA antigens against which the recipient has generated antibody, but that is limited by the number of shared grafts. The second is the development of a new cross-matching technique prior to transplantation. Attempts at immunoregulation of secreting B cell clones have been carried out using either hypertransfusions or injection of polyclonal Ig. Finally, removal and prevention of the resynthesis of HLA antibodies is a most attractive approach using immunoadsorption (IA) system with sepharose-bound protein-A columns. In our unit, fifteen ESRD patients with high levels of PRA were treated with IA. Infectious complications were not observed after IA and transplantation, and the procedure was well tolerated. In spite of the use of adjunctive immunosuppressive treatment with cyclophosphamide and prednisolone, this method produced only variable effects in lowering PRA levels, and was hampered by high de novo resynthesis of anti-HLA antibodies.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Antígenos HLA/inmunología , Inmunización , Trasplante de Riñón , Anticuerpos/aislamiento & purificación , Linfocitos B/inmunología , Supervivencia de Injerto , Prueba de Histocompatibilidad , HumanosRESUMEN
Cell surface markers of isolated graft-infiltrating cells (GIC) were studied, and functional in vitro assays performed in 8 cases of acute irreversible rejection of human renal allografts. The GIC were mostly activated T cells (OKT11+, OKT3+, Ia+), with predominance of the cytotoxic/suppressor T cell phenotype (OKT8+). A small proportion of B cells and monocytes/macrophages were also present among these GIC. The GIC were able to proliferate with lectin of allogeneic stimulation and were strongly cytotoxic toward specific donor target cells. Within the T cell subset, OKT8+ cells displayed most of the specific cytotoxicity. Despite allograft morphology typical of cellular rejection, anti-HLA complement-dependent antibodies and antibody-dependent cell cytotoxicity were found in the eluted material from rejecting kidneys. The results of our phenotypic and functional testing of unmodified GIC (no enzyme treatment, no additional culture with or without interleukin 2), show that T cells, especially OKT8+ cells, are of paramount importance in the mechanism of this type of acute irreversible rejection of human renal allografts (i.e., to the point of allograft rupture), but other potential effector mechanisms are also present in situ.
Asunto(s)
Rechazo de Injerto , Trasplante de Riñón , Linfocitos/clasificación , Antígenos de Superficie/análisis , Pruebas Inmunológicas de Citotoxicidad , Humanos , Inflamación , Riñón/patología , Lectinas/farmacología , Activación de Linfocitos/efectos de los fármacos , Linfocitos/inmunología , Macrófagos/inmunología , Monocitos/inmunología , Fenotipo , Trasplante HomólogoRESUMEN
Renal allograft tolerant patients show specific unresponsiveness in mixed-lymphocyte culture assays when confronted with donor stimulating cells. Separation of posttransplant peripheral blood lymphocytes into Fc gamma + and Fc gamma - by rosetting and into OKT8+, OKT8- by cytofluorometry enabled the demonstration of normal responses by Fc gamma - and OKT8- cells, whereas the proliferation of OKT8+ and Fc gamma + cells was depressed specifically in the presence of donor cells. Using mixing experiments, we showed that OKT8+ and Fc gamma + posttransplant lymphocytes exert a suppressive effect specific to the donor-recipient pair on the proliferative response of the pretransplant lymphocytes.
Asunto(s)
Antígenos/inmunología , Tolerancia Inmunológica , Trasplante de Riñón , Receptores Fc/inmunología , Linfocitos T Reguladores/inmunología , Inmunología del Trasplante , Adulto , Femenino , Citometría de Flujo , Humanos , Riñón/inmunología , Prueba de Cultivo Mixto de Linfocitos , Masculino , Persona de Mediana Edad , Receptores de IgG , Formación de Roseta , Donantes de Tejidos , Trasplante HomólogoRESUMEN
The immunological responsiveness of a panel of 26 consecutive cadaver kidney allograft patients with good graft tolerance was studied against cells from the specific donor. Among these 26 patients, 11 underwent acute cellular rejection and were studied during the rejection episode. An additional eight transplant patients, who lost their graft as a result of cellular rejection, were nephrectomized and studied 6 months after their return to hemodialysis as the control group of patients "at equivalent risk." A low responsiveness against the specific donor was observed in cases of good graft tolerance, but was absent during rejection and in the control group. By using mixing experiments, cells from tolerant patients were able to actively and selectively suppress the response of their autologous pretransplant cells stimulated by the specific donor cells. These suppressor cells were effective only when added during the first 48 hr of the culture and could respond at a suppressor to responder cell ratio from 1:1 to 1:4. Finally, our observations indicate that allogeneic unresponsiveness between donor-recipient pairs may be associated with the presence of suppressor cells affecting the generation of helper T cells only in the specific situation, i.e., donor-recipient, and only in cases of good graft tolerance.