Rejection of first-set skin allografts in man. the microvasculature is the critical target of the immune response.

Abstract

Recent reports of microvascular injury in delayed hypersensitivity skin reactions prompted us to reexamine the pathogenesis of first-set skin allograft rejection in man using morphologic techniques that allowed both extensive vessel sampling and unequivocal evaluation of microvascular endothelium. We here report that widespread microvascular damage is a characteristic, early consequence of the cellular immune response to first-set human skin allografts and is qualitatively similar to, but substantially more extensive than, that occurring in delayed hypersensitivity reactions. Microvascular damage in invariably preceded significant epithelial necrosis and affected initially and primarily those venules, arterioles, and small veins enveloped by lymphocytes. Vessels of both the allograft itself and the underlying graft bed (recipient tissue) were equally affected. These data suggest that endothelial cells of the microvasculature are the critical target of the immune response in first-set vascularized skin allograft rejection in man and that rejection can be attributed largely to ischemic infarction resulting from extensive microvascular damage. Other mechanisms, such as direct cellular contacts between infiltrating lymphocytes and epithelium, apparently played only a minor role. The findings presented here indicate that the rejection of first-set vascularized skin allografts, though induced by immunologically specific mechanisms, is primarily effected by final pathways that are relatively nonspecific and that may cause damage to both foreign and host vessels and cells. Rather than contradicting studies demonstrating the exquisite specificity of allograft rejection in other systems, these findings provide a further example of the heterogeneity of the cellular immune response. Recognition of the critical role of immunologically mediated microvascular injury may prove important both for an understanding of the biology of allograft rejection and for strategies aimed at prolonging allograft survival.

Biomarker evaluation of face transplant rejection: association of donor T cells with target cell injury

“…30 It is noteworthy that lymphocytic vasculitis was a prominent feature of facial transplant rejection in our study and one in keeping with early descriptions of skin allograft rejection by Dvorak et al, where the dermal microvasculature was proposed to be a primary target. 5 This feature so prominently observed in rejecting facial skin is not included in the current Banff criteria for application to face transplant rejection. 8 Although lymphocytic vasculitis is associated with reproducible endothelial degenerative alterations, including cell sloughing, Figure 4 Histopathological and immunophenotypic findings of pre-rejection, active rejection, and remission after immunosuppressive therapy.…”

“…2 The first systematic studies of any form of human allograft rejection were reported by Gibson and Medawar 3 in their classic description of skin rejection involving wartime aviators. 4 Early clues regarding the immunologic basis of skin graft rejection came from studies by Dvorak et al 5 and Bhan et al 6 that implicated both CD4 þ and CD8 þ T cells. These T-cell populations were presumed to be of recipient origin and considered to be primary effectors of epidermal and dermal microvascular target cell injury.…”

Roles for thrombin and fibrin(ogen) in cytokine/chemokine production and macrophage adhesion in vivo

“…Extravascular coagulation accompanies many Th1-associated diseases, including autoimmune neuropathologies, 1-4 glomerulonephritis, 5,6 rheumatoid arthritis, [7][8][9] Crohn's disease, 10,11 and allograft rejection. 12,13 As our studies indicate that thrombin and fibrin(ogen) function to stimulate cytokine/chemokine production and macrophage adhesion in vivo, extravascular coagulation likely exacerbates Th1-associated chronic inflammation. Thus, treatment modalities that specifically block inflammationassociated thrombin formation, fibrin deposition, and/or fibrin degradation may constitute novel approaches for controlling pathologic Th1 responses associated with autoimmunity and transplantation.…”

“…The ensuing coagulation cascade culminates with the generation of thrombin, a protease that cleaves extravasated fibrinogen, prompting its polymerization and deposition as fibrin. Accordingly, localized extravascular fibrin deposition accompanies many type 1 T helper cell (Th1)-associated responses, including autoimmune neuropathologies, [1][2][3][4] glomerulonephritis, 5,6 rheumatoid arthritis, [7][8][9] Crohn's disease, 10,11 allograft rejection, 12,13 delayed-type hypersensitivity, [14][15][16][17][18][19] and viral infections. 20,21 For some time, it has been appreciated that such Th1-associated coagulation has physiologic consequences, as the swelling that accompanies delayed-type hypersensitivity responses is suppressed in anticoagulated or fibrinogen-deficient subjects.…”

Allophenic Mice: A Pillar Awaiting Its Superstructure

“…However, neither of these seminal studies provides a fully satisfying answer. Since skin grafts and islet grafts are vascularized mainly by in-growth of blood vessels of the host and rejection first appears histologically as a perivascular collection of lymphocytes (16,17), one might have greater difficulty imagining how immune recognition connects with tissue injury. The destruction of patches of allogeneic skin and individual allogeneic islets could be owed to selective targeting of capillaries invading the graft crosspresenting allogeneic peptides.…”