Mixed chimerism achieved by a nonlethal conditioning regimen induces donor-specific tolerance to lung allografts.
BACKGROUND
Graft rejection and toxicity associated with chronic immunosuppressive therapy remain a major problem in lung transplantation (Tx). Mixed hematopoietic chimerism has been shown to produce long-lasting donor-specific transplant tolerance without immunosuppressive drugs in animal models; however, most conditioning regimens required to achieve mixed chimerism are too toxic for clinical use. The aim of this study was to develop a nonlethal conditioning regimen to induce tolerance to lung allografts.


METHODS
Four to 6-wk old ACI (RT1.A(a)) and Wistar Furth (RT1.A(u)) rats were used as organ donors and recipients, respectively. The recipient conditioning regimen included: 10 mg/animal antilymphocyte globulin (on day-5), 1 mg/kg/d tacrolimus (days 1 to 10), total body irradiation (500 cGy; day 0), and donor bone marrow (DBM) Tx (100 x 10(6) T-cell depleted cells on day 0 following irradiation). Six weeks after DBM Tx, chimeric animals received orthotopic left lung Tx. Graft survival was monitored by chest X-ray and histology.


RESULTS
Long-term DBM engraftment was observed: hematopoietic chimerism in the peripheral blood was 12.4 +/- 3.4%, 36.7 +/- 14.1%, and 31.9 +/- 14.1% at 30 d, 6 mo, and 16 mo following DBM Tx, respectively. There was no graft versus host disease. Chimeric recipients (RT1.A(u)) permanently accepted (>400 d) donor-specific lungs (RT1.A(a); n = 8), yet rapidly rejected (<8 d) third party hearts (RT1.A(l); n = 5). Graft (lung) tolerant (>150 d) chimeric recipients accepted secondary donor-specific heart grafts (>150 d; n = 4) but rejected third party heart grafts (<7 d; n = 3). Graft tolerant recipients demonstrated reduced (P < 0.05) in vitro donor-specific lymphoproliferative response and cytotoxicity, and no evidence of acute or chronic graft rejection.


CONCLUSIONS
Mixed chimerism achieved by a nonlethal conditioning regimen induced long-term donor-specific tolerance to lung allografts.
Li
Sen
S
Department of Surgery, Division of Cardiothoracic Surgery, University of Miami School of Medicine, Miami, Florida 33136, USA.
Salgar
Shashikumar K
SK
Kurimoto
Yoshihiko
Y
Yousem
Samuel
S
Pham
Si M
SM
D000818:Animals; D046528:Chimerism; D006084:Graft Rejection / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control*; D007108:Immune Tolerance; D018796:Immunoconjugates / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016040:Lung Transplantation / Q000276:immunology*; D051381:Rats; D011920:Rats, Inbred WF; D014019:Tissue Donors; D018183:Transplantation Chimera; D019172:Transplantation Conditioning / Q000379:methods*; D014181:Transplantation Immunology / Q000187:drug effects; D014184:Transplantation, Homologous
D018796:Immunoconjugates; D007166:Immunosuppressive Agents