Composite tissue allotransplantation in chimeric hosts part II. A clinically relevant protocol to induce tolerance in a rat model
| Autor: | Kaustubha A. Prabhune, Marieke Vossen, Claudio Maldonado, Diane J. Pidwell, Warren C. Breidenbach, Vijay S. Gorantla, John H. Barker, Gustavo Perez-Abadia, Cedric G. Francois, Gordon G. Wang, Luis A. Laurentin-Perez, Gary L. Anderson |
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| Rok vydání: | 2004 |
| Předmět: |
Male
medicine.medical_specialty Transplantation Conditioning medicine.medical_treatment T-Lymphocytes Rats Inbred WF Hindlimb Biology Lymphocyte Depletion Major Histocompatibility Complex medicine Animals Transplantation Homologous Transplantation Transplantation Chimera Graft Survival Limb transplantation Immunosuppression Mycophenolic Acid Mixed lymphocyte reaction Tacrolimus Surgery Rats Rats Inbred ACI Disease Models Animal medicine.anatomical_structure Drug Therapy Combination Bone marrow Immunosuppressive Agents Whole-Body Irradiation Allotransplantation |
| Zdroj: | Transplantation. 76(11) |
| ISSN: | 0041-1337 |
| Popis: | Background. We and others have shown that mixed allogeneic chimerism induces donor-specific tolerance to composite tissue allografts across major histocompatibility complex barriers without the need for immunosuppression. However, a delay period between bone marrow transplantation and limb allotransplantation is required, making such protocols impractical for clinical application. This study eliminates this delay period in a rat hind limb allotransplantation model by performing mixed allogeneic chimerism induction and transplantation “simultaneously.” Methods. Group 1 included controls in which naive Wistar Furth (WF) hosts received ACI hind limbs. Group 2 included (ACI→WF) chimeras that received limbs from third-party donors (Fisher), and group 3 included chimeras that received irradiated (1,050 cGy) ACI limbs. In group 4, WF hosts conditioned with 950 cGy received irradiated (1,050 cGy) ACI limbs followed by infusion of 100×106 ACI T-cell–depleted bone marrow cells and immunotherapy (tacrolimus and mycophenolate mofetil) for 28 days. Group 5 animals received the same treatment as group 4 animals without immunotherapy. Results. The rats in groups 1 and 2 rejected their limbs within 10 days. Only one rat in group 4 survived to the end of the study. Groups 3 and 5 demonstrated long-term limb survival without rejection or graft-versus-host disease. High levels of donor chimerism (>80%) were achieved and maintained throughout the study. Mixed lymphocyte reaction assays in both groups revealed donor-specific hyporesponsiveness with vigorous third-party reactivity. Conclusions. This study demonstrated that infusion of donor bone marrow cells into conditioned hosts immediately after limb transplantation results in stable mixed chimerism, robust tolerance, and reliable limb allograft survival. |
| Databáze: | OpenAIRE |
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