title: Contributions of direct and indirect alloresponses to chronic rejection of kidney allografts in nonhuman primates.
abstract: The relative contribution of direct and indirect allorecognition pathways to chronic rejection of allogeneic organ transplants in primates remains unclear. In this study, we evaluated T and B cell alloresponses in cynomolgus monkeys that had received combined kidney/bone marrow allografts and myeloablative immunosuppressive treatments. We measured donor-specific direct and indirect T cell responses and alloantibody production in monkeys (n = 5) that did not reject their transplant acutely but developed chronic humoral rejection (CHR) and in tolerant recipients (n = 4) that never displayed signs of CHR. All CHR recipients exhibited high levels of anti-donor Abs and mounted potent direct T cell alloresponses in vitro. Such direct alloreactivity could be detected for more than 1 y after transplantation. In contrast, only two of five monkeys with CHR had a detectable indirect alloresponse. No indirect alloresponse by T cells and no alloantibody responses were found in any of the tolerant monkeys. Only one of four tolerant monkeys displayed a direct T cell alloresponse. These observations indicate that direct T cell alloresponses can be sustained for prolonged periods posttransplantation and result in alloantibody production and chronic rejection of kidney transplants, even in the absence of detectable indirect alloreactivity.
authors.affiliation: Department of Surgery, Transplant Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Ognjenka
authors.initials: O
authors.lastname: Nadazdin
authors.forename: Svjetlan
authors.initials: S
authors.lastname: Boskovic
authors.forename: Siew-Lin
authors.initials: SL
authors.lastname: Wee
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sogawa
authors.forename: Ichiro
authors.initials: I
authors.lastname: Koyama
authors.forename: Robert B
authors.initials: RB
authors.lastname: Colvin
authors.forename: R Neal
authors.initials: RN
authors.lastname: Smith
authors.forename: Georges
authors.initials: G
authors.lastname: Tocco
authors.forename: David H
authors.initials: DH
authors.lastname: O'Connor
authors.forename: Julie A
authors.initials: JA
authors.lastname: Karl
authors.forename: Joren C
authors.initials: JC
authors.lastname: Madsen
authors.forename: David H
authors.initials: DH
authors.lastname: Sachs
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Kawai
authors.forename: A Benedict
authors.initials: AB
authors.lastname: Cosimi
authors.forename: Gilles
authors.initials: G
authors.lastname: Benichou
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002908:Chronic Disease; D018920:Coculture Techniques; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007518:Isoantibodies / Q000096:biosynthesis; D007519:Isoantigens / Q000276:immunology; D016030:Kidney Transplantation / Q000276:immunology* / Q000473:pathology; D008252:Macaca fascicularis; D011828:Radiation Chimera / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D019172:Transplantation Conditioning / Q000379:methods; D023001:Transplantation Tolerance / Q000235:genetics / Q000276:immunology
chemical_list: D007166:Immunosuppressive Agents; D007518:Isoantibodies; D007519:Isoantigens