Induction of chronic renal allograft injury by injection of a monoclonal antibody against a donor MHC Ib molecule in a nude rat model.
BACKGROUND
Chronic allograft injury induced by immunological as well as non-immunological mechanisms is still a major cause of long-term graft loss after renal transplantation. Major histocompatibility complex (MHC) incompatibilities as well as donor-specific alloantibodies are known risk factors, but the interaction of cellular and humoral mechanisms leading to allograft damage remains to be defined. The aim of this study was to analyze the impact of donor-specific post-transplant antibodies against a non-classical MHC Ib antigen apart from T-cell-dependent immune response. Therefore, we utilized a transplant rat model injecting a moAb directed against a donor MHC Ib molecule into athymic nude recipients lacking an immunocompetent T-cell system.


METHODS
F344 kidneys were transplanted into LEW.RNU rats. Donor and recipient differ in the RT1.C locus (MHC Ib) but are phenotypically identical for the RT1.A (MHC I) and RT1.B/D (MHC II) loci. A moAb directed against the donors RT1.C(lv1) was injected into recipients with stable graft function. A control group remained untreated after transplantation. The rats were monitored for renal function and grafts were analyzed for morphological changes, infiltrating cells and C4d deposition.


RESULTS
Antibody-infused rats developed renal impairment with massive urine albumin excretion. Histological changes consistent with antibody-mediated injury were interstitial fibrosis, tubular atrophy and severe glomerulopathy accompanied by an infiltrate of numerous macrophages. At time of death, grafts were negative for C4d at the peritubular capillaries and arterial endothelium.


CONCLUSIONS
Antibodies directed against a MHC Ib antigen are able to induce allograft injury in T-cell-deficient rats. This model underlines the role of non-classical MHC disparities for long-term allograft survival and demonstrates the long-term results of antibody-induced allograft damage.
Koch
Martina
M
Klinik fuer Allgemein-, Viszeral- und Transplantationschirurgie, Medizinische Hochschule Hannover, Carl-Neuberg-Str.1, 30625 Hannover, Germany. martina.koch@uke.uni-hamburg.de
Broecker
Verena
V
Heratizadeh
Annice
A
Doege
Corinna
C
Strehlau
Juergen
J
Mengel
Michael
M
Nashan
Bjoern
B
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology; D000917:Antibody Formation / Q000187:drug effects*; D002908:Chronic Disease; D003181:Complement C4 / Q000737:chemistry / Q000276:immunology; D005355:Fibrosis / Q000276:immunology / Q000473:pathology; D006084:Graft Rejection / Q000276:immunology*; D006649:Histocompatibility Antigens / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D007150:Immunohistochemistry; D007668:Kidney / Q000276:immunology / Q000473:pathology; D016030:Kidney Transplantation / Q000276:immunology* / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D011923:Rats, Nude; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D003181:Complement C4; D006649:Histocompatibility Antigens; D015395:Histocompatibility Antigens Class I; C448919:MHC Ib Qa-2 antigen; C038353:histocompatibility antigens RT, rat