Ex vivo T cell depletion (TCD), is highly effective for lethal graft-vs.-host disease (GVHD) prevention. However, T cell removal may compromise beneficial donor T cell responses. Pharmacological agents are incompletely efficacious in preventing GVHD and have significant side-effects. Rather than broadly eliminate T cells or T cell subsets, the applicants propose to functionally alter ex vivo the small proportion of donor T cells with anti-host alloreactive potential.
In aim 1, two types of ex vivo approaches are proposed to inhibit CD4+ T cell mediated GVHD lethality. The first involves physically blocking the interaction of cell surface determinants on donor T cells with those on host antigen-presenting cells. The CD40L, CD40 and CD28/B7 pathways will be targeted. The second involves targeting intracellular signalling pathways (PI3K, Jak3) required for optimal T cell responses. A series of studies using wild-type and various knockout (ko) mice are proposed in aim 1 which will investigate the mechanism(s) responsible for inducing alloantigen hyporesponsiveness.
In aim 2 A, successful tolerization approaches will be applied to CD4+ and CD8+ T cell containing donor inoculum.
In aim 2 B, T cell receptor (TCR) transgenic systems will be used to track CD4+ or CD8+ TCR clonotypes that are capable of specifically responding to alloantigen or nominal antigen. These studies will provide important information regarding the mechanism(s) responsible for tolerance induction and the specificity of these approaches as measured by bystander effects on nominal antigen responses.
In aim 2 C, the effects of tolerance induction on graft-versus-leukemia (GVL) will be analyzed using a delayed lymphocyte infusion model system. This application will provide new strategies for ex vivo GVHD prevention and will provide important data on the mechanism(s) and specificity of such approaches in clinically relevant model systems.
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