Ameliorating experimental autoimmune encephalomyelitis using immune modulators in humanized HLA-DR transgenic mice

Multiple sclerosis (MS) is an inflammatory demyelinating autoimmune disease. It occurs in young adults and is more prevalent in women. It affects approximately 2.5 million people worldwide with around 400,000 in US. There is no cure for this disease. Available treatments control acute episodes of disease but do not affect the progression of the disease. Major histocompatibility complex (MHC) class II is a cell surface molecule on antigen presenting cells, presenting peptides to T cells. In MS, these molecules present self peptides to autoreactive T cells, thereby leading to autoimmunity and destruction of myelin. To counteract this problem, specific compounds were designed to bind to MS-associated MHC class II molecules and modulate the immune response by autoreactive T cell to silence them or to inhibit their activation. This was accomplished by modulating the amino acid sequence of the self-peptides to either increase their binding or by blocking their MHC binding site. These compounds were tested in "humanized" HLA-DR transgenic mice expressing the binding domain of human HLA-DRA and HLA-DRB11501 or HLA-DRB10401 beta1 and the mouse transmembrane domain I-E (H2-E) alpha2 and beta2 in the absence of murine MHC class II molecules.

The first class of compounds are peptides designed to inhibit binding of self-peptides to the MS-associated MHC class II molecule HLA-DR2 (DRB1*1501). It was successful in treating disease in animal model of MS termed experimental autoimmune encephalomyelitis (EAE). Based on the results we achieved we propose compound PV-267 is an efficient DR2 blocker, restricting autoreactive T cells to the peripheral immune system and may not allow them to enter the central nervous system, inhibiting myelin destruction.

The alternate approach presented to inhibiting immune response was to develop a "superagonist" high affinity analog of the immunodominant HLA-DR4 (DRB1*0401) restricted MBP 111-129 peptide to silence pathogenic T cells.