Establishing A Linear Program for the Development of Costimulation Resistant T-Cells
Synopsis: Belatacept is an alternative for calcineurin-inhibitors in transplantation. It binds B7 costimulation molecules, CD80 and CD86, blocking their interactions with CD28 and depriving naïve T-cells of signals required for activation. Although belatacept is effective in most patients, a sizable minority of patients experience T-cell-mediated rejection. A growing body of work suggests that these rejections stem from the actions of memory T-cells with diminished co-stimulatory requirements. Indeed, studies from our lab, and others, have identified phenotypic characteristics of maturing T-cells that associate with belatacept resistance, including complete loss of CD28 expression. We have shown that these cells proliferate and produce high levels of effector cytokines when stimulated with alloantigen.
Our hypothesis is that upon stimulation, naïve T-cells begin down a path that progressively reduces their need for CD28-B7 costimulation, endowing them with a phenotype of belatacept resistance. We posit that this maturation is linear and anticipatable, and the movement from co-stimulation dependence to independence involves specific, time-dependent signals, which lead to tractable changes in surface molecule expression with prognostic and therapeutic value.
We will test this hypothesis, focusing on the acquisition of a specific surface marker, CD57, which we have shown to associate with human costimulation resistant rejection. Aim 1 will define a linear maturation scheme leading to CD57 acquisition and relate this to belatacept resistance. Aim 2 will examine the impact of immunosuppressant exposure at various stages along the differentiation pathway mapped in Aim 1, with specific attention to the differential effects of calcineurin inhibition versus mTOR inhibition.