Lung and heart transplants are more immunogenic, and less prone to tolerance induction than kidney transplants. We and others have shown that an autoimmune Th17 and B cell response to collagen type V (?1)(col V) and K?1tubulin often accompanies lung transplantation, while heart transplantation elicits a response to col V and vimentin. The risks associated with de novo autoimmunity to Col V, k?1tubulin, and vimentin are substantial - for example, post-transplant Th17 responses to col V were associated with a 10-fold higher risk of the most severe form of fibro-obliterative chronic rejection in lung transplants, known as bronchiolitis obliterans syndrome [BOS]. Why these particular self-antigens and not others are the main targets of autoimmunity in lung and heart transplants, is currently unknown. We recently discovered that memory-type Th17 immune responses to col V, k?1tubulin, and vimentin are revealed in normal healthy individuals upon removal of CD39+ regulatory T cells (Tregs) or blocking various Treg functions. This suggests that autoimmunity, rather than being a secondary consequence of alloimmunity, may precede alloimmunity in the case of heart & lung transplants. We propose to test the hypothesis that Col V, k?1tubulin, and vimentin-reactive T cells are natural type 17 TcR?? memory T cells, produced in the thymus during ontogeny along with natural Treg (nTreg) counterparts, the normal function of which lies in maintaining airway and vascular homeostasis. This hypothesis represents a paradigm shift in the current view of donor passenger T cells in heart & lung allografts, from that of an inconsequential component of graft immunogenicity, to that of a necessary component of successful graft outcome. We propose 3 specific aims: 1) to further characterize the human natural T memory response to col V, k?1tubulin, and vimentin; 2) to determine the intrathymic derivation and organ-specificity of nTh17 specific to these antigens; and 3) to determine whether, and if so, how, the transplant donor immune status vis a vis col V, k?1tubulin, and vimentin, and donor HLA-DR type influences transplant outcome, and whether manipulation of donor or donor MHCII-restricted host immune status can prevent acute/ chronic rejection, caused by induced (i)Th17 cells and B cells specific for col V . Incorporating natural Th17 and regulatory T cells in the overall strategy of immune management of the graft recipient may preserve well-regulated autoimmunity to col V, k?1tubulin, and vimentin and allow stable tolerance to develop.
Lung and heart transplants are prone to a type of graft failure that resembles excessive scar formation, obliterating the spaces reserved normally for blood and air flow. We have found that a tightly controlled immune response to 3 components of normal vessels and airways, col V, k?1tubulin, and vimentin, is a normal feature of all healthy individuals. We propose to test how immune cells specific for these 3 self-proteins arise during normal development, and how this tightly controlled response becomes uncontrolled response in the lung transplant recipient, leading to loss of the graft and patient death. If successful, lug and heart transplant patients will benefit from less global, more local immunosuppressive strategies targeted to these cells.
|Haynes, Lynn D; Julliard, Walker A; Mezrich, Joshua D et al. (2018) Specific Donor HLA-DR Types Correlate With Altered Susceptibility to Development of Chronic Lung Allograft Dysfunction. Transplantation 102:1132-1138|
|Sullivan, J A; Jankowska-Gan, E; Hegde, S et al. (2017) Th17 Responses to Collagen Type V, k?1-Tubulin, and Vimentin Are Present Early in Human Development and Persist Throughout Life. Am J Transplant 17:944-956|
|Agashe, Vrushali V; Burlingham, William J (2015) Autoimmune Reactivity in Graft Injury: Player or Bystander? Curr Transplant Rep 2:211-221|