Prof. Richard N Mitchell

The Mitchell laboratory conducts research at the interface of immunology and vascular cell biology. Focusing on the mechanisms underlying acute and chronic rejection in solid organ allografts, the work involves mouse transplant models, as well as human clinical transplantation, focusing on understanding specific immunologic pathways that drive rejection and ultimately graft failure. The laboratory is particularly interested in the mechanisms that induce the process of allograft arteriopathy whereby allograft vessels become progressively more occluded until the grafts suffer irreversible ischemic injury. The research may have much broader applicability, since the inflammatory mediators that drive the occlusive process in transplants may also be involved in mediating the vascular wall thickening that characterizes more “typical” atherosclerosis. The laboratory uses several different strains of genetically engineered mice, deficient either in cell surface molecules that promote the cellular cross-talk necessary to promote rejection, or lacking particular cytokine or chemokine mediators or their receptors. In collaboration with other members of the Harvard and MIT communities, as well as industry (Schering-Plough, Bristol Myers-Squibb, and Novartis) the group has also evaluated promising interventions to prevent allograft arteriopathy.

A major laboratory focus involves characterizing the intragraft cytokine milieu, and understanding its effect on solid organ allograft survival and pathology. Although we initially sought to demonstrate a dichotomy in the effects of so-called Th1 and Th2 cytokines in allograft rejection, the reality is considerably less straightforward Thus, absence of interferon-γ ameliorates the development of allograft arteriopathy, but also promotes a more aggressive acute parenchymal rejection.

The group has also been interested in identifying the source of precursor or stem cells that are recruited to sites of vascular injury. Long thought to derive from the underlying vascular medial smooth muscle cells, it is now clear that intimal cells in vascular pathologic lesions (both chronic rejection and atherosclerosis) can be derived from circulating host cells, including a significant number from host bone marrow precursors. This paradigm shift has important implications for transplantation, as well as for treating the complications of atherosclerosis: intervention can potentially be focused on preventing the recruitment and/or attachment of the circulating precursors at sites of injury (J. Immunol. 2000; 165: 3506-3518; Nature Med. 2001; 7:738-741; Atherosclerosis 2006; 9: 351-362).

The group has also examined the role of the cytokine environment within vessel walls specifically, and its effect on vascular wall remodeling. The findings developed from an aortic interposition model of aortic aneurysm represent a significant revision of previous thinking that Th1 cytokines are the critical determinants for medial degeneration during aneurysm formation. The research has important implications not only for understanding the development of human abdominal aortic aneurysms, but also for the positive remodeling that maintains luminal diameter at early stages of atherosclerosis (J Clin Invest. 2004;114:300-8; Circ. Res. 2007;100:967-978).