gms | German Medical Science

121. Kongress der Deutschen Gesellschaft für Chirurgie

Deutsche Gesellschaft für Chirurgie

27. bis 30.04.2004, Berlin

Pre-transplant Donor-specifc Transfusions combined with Cyclosporine induce Tolerance to MHC class I-mismatched Cardiac Allografts in Miniature Swine

Vortrag

  • presenting/speaker Ruediger Hoerbelt - Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital, Boston, USA; Klinik fuer Allgemein- und Thoraxchirugie, Justus-Liebig-Universitaet, Giessen, Deutschland
  • T. Shoji - Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital, Boston, USA
  • D.R. Johnston - Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital, Boston, USA
  • W. Padberg - Klinik fuer Allgemein- und Thoraxchirugie, Justus-Liebig-Universitaet, Giessen, Deutschland
  • D.H. Sachs - Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital, Boston, USA
  • J.C. Madsen - Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital, Boston, USA

Deutsche Gesellschaft für Chirurgie. 121. Kongress der Deutschen Gesellschaft für Chirurgie. Berlin, 27.-30.04.2004. Düsseldorf, Köln: German Medical Science; 2004. Doc04dgch0319

Die elektronische Version dieses Artikels ist vollständig und ist verfügbar unter: http://www.egms.de/de/meetings/dgch2004/04dgch113.shtml

Veröffentlicht: 7. Oktober 2004

© 2004 Hoerbelt et al.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.de). Er darf vervielf&aauml;ltigt, verbreitet und &oauml;ffentlich zug&aauml;nglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.


Gliederung

Text

Introduction

To evaluate the effect of pre-transplant donor-specific transfusion on sensitization and tolerance induction to cardiac allografts in a clinically relevant large-animal model.

Materials and methods

Heterotopic cardiac transplants were performed across a major histocompatibility complex (MHC) class I barrier in MGH inbred miniature swine. Experimental animals were treated with two donor-specific transfusions (DSTs), each containing 1.4x108 viable peripheral blood mononuclear cells, 14 and 7 days prior to heart transplantation. All animals received a 12-day course of cyclosporine (CyA) (trough level 300-500 ng/ml) starting on post-operative day (POD) 0. Control groups received CyA alone, DST alone or no treatment. Cell mediated lympholysis (CML) assays were performed at regular basis. T cell priming and activation induced cell death (AICD) were assessed by carboxyfluoroscein succinimidyl ester (CFSE) proliferation assays and Annexin V staining. Rejection was monitored by serial biopsies.

Results

Untreated (n=2) and DST-only (n=2) treated control animals rejected between POD 6 and 8. Animals treated with CyA alone (n=3) exhibited graft survival to 53, 52 and 59 days. In contrast, the combination of DST-preteatment and CyA (n=3) led to stable graft function for >200, >75, and >85 days. Grafts in both the control and experimental groups showed equally severe cellular infiltrates on POD 28 and 50 (ISHLT 1b to 3b/4). However, in the control groups, rejection continued to worsen over time, whereas in the experimental group, the cellular infiltrate diminished over time (ISHLT 0/4 on POD 100 and 200). Like the controls, experimental animals maintained peripheral CML response against donor and third party antigen. Following two DSTs, CD4+ and CD8+ recipient T cells demonstrated an increased donor-specific proliferative response on CFSE assay (CD4+: 29.9% anti-donor, 16.4% anti-third-party; CD8+: 45.9% anti-donor, 31.5% anti-third-party; n=6). There was no difference in the rate of dividing T cells undergoing AICD in response to donor versus third-party antigen stimulation by Annexin V staining. None of the animals developed anti-donor antibodies following DST treatment.

Conclusion

The combination of pre-transplant DST and a short course of CyA appears to facilitate tolerance to MHC class I disparate cardiac allografts in a preclinical miniature swine model. The sustained peripheral anti-donor CML response and the fact that alloreactive T cells were primed by the DST prior to transplantation suggest an active regulatory mechanism rather than peripheral deletion.