Manipulation of cytokines as a novel approach to overcome xenotransplant rejection

The current overwhelming unmet demand for donor organs warrants the search for alternative sources. Pig-to-human xenotransplantation represents a promising approach; however, before this solution can be realized, there are many immunological hurdles to overcome. The first of those hurdles, hyperacute rejection, has been overcome only to uncover another rejection profile that is unresponsive to current immunotherapies - acute vascular rejection. We have shown that manipulation of cytokine profiles, and, accordingly, T cell polarization, is an effective method of down-regulating acute vascular rejection to cell-mediated rejection, which can then be managed with available antirejection treatments. The inherent nature of cytokines, specifically their short half-lives, multicomponent receptor systems, and nonspecific effects, presents limitations in the use of therapeutic cytokine modulation. For this reason, modulation therapies that target cells producing cytokines, instead of the cytokines themselves, represent a novel approach which would eliminate these aforementioned problems. We have found that transfer of distinct dendritic cell subsets and control of dendritic cell-mediated costimulation can effectively direct the cytokine profile and change an acute vascular xenorejection profile to cell-mediated rejection, which is responsive to immunotherapy.