Differential induction of experimental autoimmune encephalomyelitis by myelin basic protein molecular mimics in mice humanized for HLA-DR2 and an MBP(85-99)-specific T cell receptor.

Multiple sclerosis (MS) is a chronic autoimmune neurological disease characterized by infiltration of peripheral inflammatory cells to the central nervous system (CNS) and demyelination of CNS white matter. Epidemiological evidence suggests a possible infectious trigger. One potential mechanism by which an infectious agent may trigger MS is via molecular mimicry wherein T cells generated against foreign epitopes cross-react with self-myelin epitopes, such as myelin basic protein (MBP), with sufficient sequence similarity.

ECDI-fixed allogeneic splenocytes induce donor-specific tolerance for long-term survival of islet transplants via two distinct mechanisms.

A major challenge for human allogeneic islet transplantation is the development of effective methods to induce donor-specific tolerance to obviate the need for life-long immunosuppression that is toxic to the insulin-producing beta cells and detrimental to the host. We developed an efficient donor-specific tolerance therapy that utilizes infusions of ethylene carbodiimide (ECDI)-treated donor splenic antigen-presenting cells that results in indefinite survival of allogeneic islet grafts in the absence of immunosuppression. Furthermore, we show that induction of tolerance is critically dependent on synergistic effects between an intact programmed death 1 receptor-programmed death ligand 1 signaling pathway and CD4(+)CD25(+)Foxp3(+) regulatory T cells.

Cross-reactivity between peptide mimics of the immunodominant myelin proteolipid protein epitope PLP139-151: comparison of peptide priming in CFA vs. viral delivery.

Epidemiological evidence suggests that pathogens may trigger the development of autoimmune diseases such as multiple sclerosis (MS). Pathogens may trigger disease via molecular mimicry, wherein T cells generated against foreign epitopes are also cross-reactive with self-epitopes. Five pathogen-derived molecular mimics of PLP(139-151) (the immunodominant CD4(+) T cell myelin epitope in SJL mice) were previously identified.

Structural requirements for initiation of cross-reactivity and CNS autoimmunity with a PLP139-151 mimic peptide derived from murine hepatitis virus.

MS is an autoimmune CNS demyelinating disease in which infection appears to be an important pathogenic factor. Molecular mimicry, the cross-activation of autoreactive T cells by mimic peptides from infectious agents, is a possible explanation for infection-induced autoimmunity. Infection of mice with a non-pathogenic strain of Theiler's murine encephalomyelitis virus (TMEV) engineered to express an epitope from Haemophilus influenzae (HI) sharing 6/13 amino acids with the dominant proteolipid protein (PLP) epitope, PLP139-151, can induce CNS autoimmune disease.

Cutting Edge: Anti-CD25 monoclonal antibody injection results in the functional inactivation, not depletion, of CD4+CD25+ T regulatory cells.

CD4+CD25+ T regulatory (T(R)) cells are an important regulatory component of the adaptive immune system that limit autoreactive T cell responses in various models of autoimmunity. This knowledge was generated by previous studies from our lab and others using T(R) cell supplementation and depletion. Contrary to dogma, we report here that injection of anti-CD25 mAb results in the functional inactivation, not depletion, of T(R) cells, resulting in exacerbated autoimmune disease.