RESUMEN
BACKGROUND: The aim of this study was to evaluate the risks of sensitization by islet grafts encapsulated in a bilaminar immunoprotective membrane. METHODS: We studied five groups of Lewis rats: one control group (no islets), two groups that received free islets (200 or 1000 s.c.), and two groups that received encapsulated ones (200 or 1000 s.c.) from Dark Agouti (DA) rats. Four weeks later, abdominal heterotopic DA-heart transplantation was performed on the same recipients. The time-to-heart graft rejection was assessed by the cessation of heart contractions. Rejection was confirmed by histological examinations. Antidonor antibodies were determined by fluorescence activated cell sorter (FACS) analysis. RESULTS: The control animals had a mean heart graft survival of 6.4 days. The free islet groups had significantly shorter heart graft survivals-i.e., 4.8 days (200 islets) and 1.0 day (1000 islets) (P < 0.001)-while those of the encapsulated islet groups were about the same as that of the control group-i.e., 6.4 days (200 islets) and 6.0 days (1000 islets). In the free islet groups, anti-DA antibodies developed in 7/10 (200 islets) and 8/8 (1000 islets) animals after the islet transplantation. In the encapsulated groups, 1/10 (200 islets) and 3/8 (1000 islets) animals developed anti-DA antibodies after these transplantations. All animals had anti-DA antibodies at the time of heart graft rejection. On histological examination all grafts showed various features of rejection. CONCLUSIONS: The bilaminar membrane protects against sensitization and prevents accelerated rejection of a subsequent vascularized graft, at least during the first month after the islet transplantation.
Asunto(s)
Trasplante de Islotes Pancreáticos/inmunología , Politetrafluoroetileno , Animales , Anticuerpos/inmunología , Formación de Anticuerpos/inmunología , Supervivencia de Injerto/inmunología , Trasplante de Corazón/inmunología , Trasplante de Islotes Pancreáticos/patología , Ratas , Donantes de Tejidos , Trasplante Homólogo/inmunologíaRESUMEN
Immunity to autologous protein has not previously been described following nonhuman primate cardiac transplant. Native hearts and cardiac allografts from cynomolgus monkeys were assessed by immunohistology for vimentin, a highly conserved intermediate filament protein. IgM and IgG to vimentin were measured in serial sera from untreated (n = 4) or cyclosporine (CsA)-treated (n = 8, 2 with ATG) cardiac allograft recipients, and in groups treated with anti-CD154 antibody with (n = 6) or without ATG (n = 28). IgM or IgG reactive with vimentin was elaborated within 30 days with unmodified acute rejection (3/4) or in CsA-treated animals (5/6). CD154 blockade did not prevent anti-vimentin IgM (14/28) but tended to delay the IgG response during therapy (anti-CD154: 8/28, p = 0.10 vs. CsA; anti-CD154+ATG: 2/6). CAV and alloantibody were seen in 25 of 26 animals with grafts surviving over 30 days, including seven animals without increasing anti-vimentin antibody. Anti-vimentin antibodies and vascular complement deposition were found in rejected hearts. Acute and chronic alloimmunity disrupt modulation of autoreactivity to vimentin through pathways, which are resistant to CsA, but may be partially regulated by CD154.
Asunto(s)
Formación de Anticuerpos , Trasplante de Corazón/métodos , Trasplante Homólogo/métodos , Vimentina/farmacología , Animales , Western Blotting , Ligando de CD40/biosíntesis , Núcleo Celular/metabolismo , Activación de Complemento , Complemento C4b/inmunología , Ciclosporina/farmacología , Citoplasma/metabolismo , Rechazo de Injerto , Supervivencia de Injerto , Humanos , Inmunoglobulina G/química , Inmunoglobulina M/química , Inmunohistoquímica , Inmunosupresores/farmacología , Vacunas contra la Influenza/farmacología , Isoanticuerpos/química , Macaca fascicularis , Miocardio/metabolismo , Miocardio/patología , Fragmentos de Péptidos/inmunología , Primates , Factores de Tiempo , Vimentina/química , Vimentina/inmunologíaRESUMEN
BACKGROUND: The pathophysiology of hyperacute lung rejection (HALR) is not fully understood. A mouse model of HALR by human blood would be valuable to efficiently dissect the molecular mechanisms underlying this complex process, but it has not been described. METHODS: We developed a xenogenic mouse lung-perfusion model. Perfusion with heparinized autologous blood (n=3) was compared with human blood unmodified (n=7) or pretreated with C1 inhibitor (n=5) or soluble complement receptor type 1 (n=6) at unchanged flow conditions. RESULTS: Perfusion with autologous blood was associated with stable physiologic parameters and no overt evidence of lung injury for up to 2 hr. Pulmonary artery perfusion pressure increased rapidly after introduction of unmodified human blood, plasma anti-Gal(alpha)1,3Gal antibodies declined (90% immunoglobulin [Ig]M, 80% IgG), and lungs reliably met survival endpoints within 11 min (median 10 min, confidence interval [CI]: 9-11). Human Ig and neutrophils were rapidly sequestered in the lung. Survival was significantly prolonged in the soluble complement receptor type 1 group (36 min, CI: 26-46) (P<0.01) and in the C1 inhibitor group (23 min, CI: 21-25) (P<0.05), and pulmonary vascular resistance elevation and complement activation were significantly attenuated but not prevented. CONCLUSIONS: Hyperacute rejection of mouse lung by human blood occurs with kinetics, physiology, and histology closely analogous to the pig-to-human model. In addition, as in that model, neither of two potent soluble-phase complement inhibitors prevented complement activation or HALR. We conclude that the mouse lung model is relevant to dissect the cellular and molecular mechanisms governing HALR.