Non-myeloablative Immunosuppression Prevents Rejection of Vascularized Composite Allografts
Byoungchol Oh, Ph.D., Georg J. Furtmüllerr, MD, Marcos Iglesias, Ph.D., Madeline Fryer, B.S., Damon Cooney, M.D., Ph.D., W.P. Andrew Lee, M.D., Giorgio Raimondi, PH.D., Gerald Brandacher, M.D..
Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Reconstructive transplantation represents a valid therapeutic option after devastating tissue loss. Routine clinical application of this approach, however, is hampered by the toxicity of long-term maintenance immunosuppression. The current study investigated a novel short-term immunomodulatory strategy in a murine hind limb transplantation model.
Fully MHC-mismatched orthotopic hind limb transplants were performed from Balb/C to C57BL/6 mice. Recipient animals received combinations of: T-depleting mAb, CTLA4-Ig, and Rapamycin (POD0-9). Flow cytometric analysis was performed to evaluate mixed chimerism and clonal deletion of alloreactive T cells.
CTLA4 Ig treated group showed increased graft survival compared to the non-treated controls. Combination of T cell depletion and CTLA4-Ig plus short-course of Rapamycin increased VCA survival significantly (MST 105 days; p<0.01). Mixed chimerism was detected in recipients receiving the combined treatment protocol with 5.013 ± 1.23 % of donor derived CD11b+ cells on POD 55. Vβ - TCR staining profiles in recipients after full treatment showed 1.570 ± 0.3700 % of νβ5+CD4+ T cells, while naïve C57BL/6 express 3.567 ± 0.3690 % of νβ5+CD4+ T cells, suggesting the actuation of central deletion of developing donor-reactive T cells. Graft-Infiltrating Foxp3+ regulatory T cells of donor origin were detected on POD60 suggesting an important regulatory role exerted by donor Treg.
This study shows that the combination of T cell depletion, costimulation blockade, and a short-course of Rapamycin prevents VCA rejection and significantly prolongs graft survival without myeloablative conditioning. Immuneregulation appears to rely on the combined effect of mixed chimerism and regulatory T cells.
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