Mixed Chimerism Achieved by a Nonlethal Conditioning Regimen Induces Donor-Specific Tolerance to Lung Allografts
| Autor: | Sen Li, Samuel A. Yousem, Si M. Pham, Yoshihiko Kurimoto, Shashikumar K. Salgar |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Graft Rejection
medicine.medical_specialty Immunoconjugates Transplantation Conditioning medicine.medical_treatment Urology Rats Inbred WF Chimerism Immune tolerance Transplantation Immunology Immune Tolerance Animals Transplantation Homologous Medicine Lung transplantation Transplantation Chimera business.industry Total body irradiation medicine.disease Tissue Donors Tacrolimus Rats Surgery Transplantation Graft-versus-host disease medicine.anatomical_structure Bone marrow business Immunosuppressive Agents Lung Transplantation |
| Zdroj: | Journal of Surgical Research. 146:289-297 |
| ISSN: | 0022-4804 |
| DOI: | 10.1016/j.jss.2007.07.017 |
| Popis: | 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.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.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 (P0.05) in vitro donor-specific lymphoproliferative response and cytotoxicity, and no evidence of acute or chronic graft rejection.Mixed chimerism achieved by a nonlethal conditioning regimen induced long-term donor-specific tolerance to lung allografts. |
| Databáze: | OpenAIRE |
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