Victor E. Kotelianski

|[alpha]|1|[beta]|1 integrin is crucial for accumulation of epidermal T cells and the development of psoriasis

Psoriasis is a common T cell–mediated autoimmune inflammatory disease. We show that blocking the interaction of α1β1 integrin (VLA-1) with collagen prevented accumulation of epidermal T cells and immunopathology of psoriasis. α1β1 integrin, a major collagen-binding surface receptor, was exclusively expressed by epidermal but not dermal T cells. α1β1-positive T cells showed characteristic surface markers of effector memory cells and contained high levels of interferon-γ but not interleukin-4. Blockade of α1β1 inhibited migration of T cells into the epidermis in a clinically relevant xenotransplantation model. This was paralleled by a complete inhibition of psoriasis development, comparable to that caused by tumor necrosis factor-α blockers. These results define a crucial role for α1β1 in controlling the accumulation of epidermal type 1 polarized effector memory T cells in a common human immunopathology and provide the basis for new strategies in psoriasis treatment focusing on T cell–extracellular matrix interactions.

Integrin α1β1 and Transforming Growth Factor-β1 Play Distinct Roles in Alport Glomerular Pathogenesis and Serve as Dual Targets for Metabolic Therapy

Alport syndrome is a genetic disorder resulting from mutations in type IV collagen genes. The defect results in pathological changes in kidney glomerular and inner-ear basement membranes. In the kidney, progressive glomerulonephritis culminates in tubulointerstitial fibrosis and death. Using gene knockout-mouse models, we demonstrate that two different pathways, one mediated by transforming growth factor (TGF)-β1 and the other by integrin α1β1, affect Alport glomerular pathogenesis in distinct ways. In Alport mice that are also null for integrin α1 expression, expansion of the mesangial matrix and podocyte foot process effacement are attenuated. The novel observation of nonnative laminin isoforms (laminin-2 and/or laminin-4) accumulating in the glomerular basement membrane of Alport mice is markedly reduced in the double knockouts. The second pathway, mediated by TGF-β1, was blocked using a soluble fusion protein comprising the extracellular domain of the TGF-β1 type II receptor. This inhibitor prevents focal thickening of the glomerular basement membrane, but does not prevent effacement of the podocyte foot processes. If both integrin α1β1 and TGF-β1 pathways are functionally inhibited, glomerular foot process and glomerular basement membrane morphology are primarily restored and renal function is markedly improved. These data suggest that integrin α1β1 and TGF-β1 may provide useful targets for a dual therapy aimed at slowing disease progression in Alport glomerulonephritis.