Development of Allogeneic Hair Transplantation by Antigen-specific Immune Tolerance

Abstract

Severe permanent alopecia patients cannot benefit from autologous hair transplantation because of the shortage of donor hair follicles (HFs). Therefore, allogeneic hair transplantation is considered as an alternative option, but the generalized immunosuppression cannot be justified for the non-life-threatening disease. For the development of allogeneic hair transplantation with antigen-specific immune tolerance, the dendritic cell (DCs) is focused as a key target for tolerance induction. The alloantigen presentation by immature DCs or the depletion of donor resident DCs can be new immunomodulatory strategy for the prevention of rejection process. In this study, the tolerogenic potential of anti-ICAM1 antibody (MD-3) and the immunomodulatory effect of UVB pre-irradiation plus anti-CD154 antibody treatment was evaluated under the skin immune system in MHC-mismatched HF allograft model in nonhuman primates and humanized mouse. In the first part, following the preparation of recipient sites with a hair-removing diode laser, donor HFs from monkeys thick eyebrow were transplanted into recipient back skin under the treatment of MD-3 antibody and short-term immunosuppressant (IS). The survival of HF allografts was significantly enhanced in MD-3 treatment group, whereas rapidly impaired in the immunosuppressant only and control groups. On histological examination, the outer root sheath of HF allograft was maintained over several weeks in the MD-3 treatment group, whereas rapidly destroyed in the control group. Although long-term survival was not achieved, MD-3 treatment markedly enhanced HF allograft survival by the delayed and diminished perifollicular T cell infiltration. In the second part, humanized mice were generated by the infusion of human CD34+ hematopoietic stem cells into NOD/Lt-scid IL2rγ null mice, then incubated for 16 weeks to repopulate the human immune system. UVB was pre-irradiated to donor HFs to make tissue resident donor DCs migrate out of donor tissue, and anti-CD154 antibody was treated to recipient humanized mice to block the maturation of recipient DCs and co-stimulatory signaling during direct and indirect antigen presentation pathway. Surprisingly, the long-term survival of HF allografts was achieved showing normal hair cycle with newly growing black pigmented hair shafts. In the first part, anti-ICAM1 antibody combined with short-term rapamycin treatment enhanced the HF allograft survival in nonhuman primate model. This attempt efficiently suppressed alloreactive T cell response, but only targeted to the recipient immune system. In the second part, we observed the long-term survival of HF allograft achieved under the UVB pre-irradiation to the donor HFs by significantly diminishing alloreactive T cell infiltration in humanized mouse model. In conclusion, the induction of antigen-specific T cell tolerance by MD-3 antibody or UVB pre-irradiation could be adopted in the skin immune system and these can be a potent immunomodulatory tool for preventing allograft rejection.