Use of Topical Immunosuppressive Drugs for the Induction of Tolerance to Allogeneic Skin Transplantation
Solid organ transplantation may be life-saving treatment for individuals with illnesses that have caused organ failure. Organ transplantation can also significantly improve the quality of life in these patients. However, a challenge remains in preventing graft rejection and eventual graft loss. Allogeneic graft (graft from another individual of the same species) rejection is initiated by the recognition of donor proteins expressed in the graft by attacker T cells of the recipient. Studies characterizing the immune status of patients where immunosuppressive drug treatments delay or prevent graft loss suggest that regulatory immune cells, such as regulatory T cells, play a role. Therefore, inducing immunological tolerance may be a solution to decrease the load of immunosuppressive drugs needed to maintain graft survival. We would like to develop a safe and reliable method of inducing regulatory T cells for the modulation of immune responses.
Our overall hypothesis was that topical immune modulation using creams such as calcipotriol (vitamin D derivative), betamethasone diproprionate (topical steroid) or both at the time of injection of cells from a transplant donor into the skin would promote regulatory T cell-mediated tolerance to allogeneic skin grafts and may be used to ultimately prevent or delay acute/chronic graft rejection. We proposed 2 aims for this preliminary work: 1) To optimize the regimen for the generation of polyclonal and antigen-specific regulatory T cells with topical application of calcipotriol and betamethasone diproprionate; 2) To explore the effectiveness of topical calcipotriol and betamethasone diproprionate induced tolerance to transplanted skin allograft
During the past year we have made the following progress towards these 2 aims: We have tested the three rub-on formulations of immunomodulatory drugs for their ability to induce regulatory T cells. Using spleen cells from transplant donors that expressed a foreign protein to inject into the skin – a technique simpler than whole skin transplantation, we found rapidly dividing regulatory T cells in the skin draining lymph nodes of mice that were transplanted with donor cells and treated with two of the three drugs, both containing the corticosteroid betamethasone diproprionate. Using a test that is similar to a skin prick test for allergies, the ears of these mice were tested for how their body would react to a foreign protein (which is found on transplanted organs). Mice that were treated with formulations containing corticosteroid had minimal swelling of the ear. In addition, less attacker T cells were found in the cervical lymph nodes. This suggested that the immune system of these mice was modulated and their reaction to foreign proteins was suppressed. When foreign skin was transplanted onto these mice, the graft was still rejected indicating that further optimization of the tolerance-inducing treatment schedule needs to be performed. Our plan is to next characterize the population of regulatory T cells in terms of their longevity, location in the body, and ability to suppress the immune system. We will then repeatedly expose the animals to the foreign protein to mimic the continuous exposure to the transplanted organ to determine when tolerance will break and how the immune system changes over time.