The long-term goal of our research is to develop better strategies to manipulate interactions between
dystrophic muscle and the immune system, so that the pathology of Duchenne muscular dystrophy (DMD) can
be reduced. As our knowledge of the interactions between the immune system and dystrophic muscle has
grown, several distinct mechanisms through which immune cells promote damage of dystrophic muscle have
been identified. However, we have also learned that specific populations of immune cells, including some
macrophage subpopulations and regulatory T-cells, promote muscle growth and regeneration in muscular
dystrophy. Because the activation, phenotype and function of immune cells that affect muscular dystrophy are
strongly influenced by costimulatory signals that are exchanged between myeloid cells and lymphoid cells,
interventions that target costimulatory pathways have the capacity to influence the balance between
detrimental and pro-regenerative processes that are mediated by immune cells in dystrophic muscle.
Cytotoxic T-lymphocyte-associated protein 4 (CTLA4) is a particularly important costimulatory molecule that
influences interactions between immune cells. Manipulation of CTLA4 availability to mediate signaling between
myeloid and lymphoid cells greatly influences the magnitude and quality of the immune response to diseased
tissue. Our preliminary findings support the hypothesis that administration of a recombinant fusion protein
containing CTLA4 profoundly influences the immune response to dystrophic muscle and reduces muscle
damage. In the investigation proposed here, we will test that hypothesis, determine the mechanisms through
which CTLA4-mediated interventions affect muscular dystrophy and evaluate the safety and efficacy of long-
term administration of exogenous CTLA4 in the mdx mouse model of DMD.
Aim 1. Test the hypothesis that treatments with CTLA4-immunoglobin fusion protein (CTLA4-Ig) produce long-
term reductions in muscle pathology and improve function in mouse models of DMD.
Aim 2. Test the hypothesis that CTLA4-Ig acts on both lymphoid and myeloid cells to reduce muscle injury and
inflammation and promote a pro-regenerative environment in dystrophic muscle.
Aim 3. Assess safety and long-term effects of CTLA4-Ig administration on immune cell function.
Together, these findings can enable us to determine whether CTLA4-Ig, a drug that is safe and efficacious for
the treatment of other human diseases, can provide a successful, new strategy for treating DMD.