Skin disease, Skin and cardiac allograft rejection, T cell recruitment to inflammation in peripheral tissues
Development and effector function of CD8+ T cells in contact hypersensitivity
Innate immune mechanisms regulating T cell recruitment in contact hypersensitivity
Role of chemokines in acute allograft rejection
Epidermal application of reactive haptens such as urushiol, the reactive agent in poison ivy, and subsequent challenge results in the development of a T cell mediated inflammatory response termed allergic contact dermatitis or contact hypersensitivity (CHS). Using several different strategies we have observed that hapten application primes two reactive T cell populations: IFN-g producing CD8+ T cells which are the effector T cells of the response and CD4+ T cells producing IL-4, IL-5 and IL-10 which regulate the magnitude and duration of the CHS response. Once primed, recruitment of the CD4+ and CD8+ T cells to tissue challenge sites requires a complex cascade of chemokine production and leukocyte infiltration. This cascade is initiated when hapten induces keratinocytes to produce chemoattractants such as Groa which recruit neutrophils to the challenge site. The goal of our studies is to define the neutrophil derived products and/or activities which lead to the recruitment of the hapten-primed T cells to the site and the effector functions expressed by the T cells following activation by the hapten at the site to elicit the CHS response.
Transplantation of allogeneic tissues primes populations of T cells with specificity to alloantigens expressed by the graft. The transplant surgery inherently causes tissue trauma which includes mechanical tissue injury and ischemia-reperfusion injury. This trauma induces two cascades of chemokine production within the allograft tissue. The first cascade begins very shortly after transplantation and is composed of chemokines that recruit leukocytes involved in the wound healing process such as neutrophils and macrophages. As this cascade subsides a second cascade begins that is comprised of chemokines which recruit the alloantigen-primed T cells to the graft site. Our recent results have indicated the interactions of the two cascades and the ability to inhibit T cell infiltration into allografts and to inhibit acute rejection by antagonism of either early or late chemokines. The goal of these studies is to better understand the process of T cell recruitment to allografts and tissue infiltration. This should aid in the development of strategies to prolong the health and function of transplanted organ allografts.
Anton Gorbachev, Ph.D.
Danielle Kish, B.S.
Peter S. Heeger, M.D., Dept. Medicine, Mt. Sinai School of Medicine, New