Your nose knows how to target brain inflammation

Currently approved therapies for multiple sclerosis and other chronic inflammatory diseases dampen proinflammatory immune responses, but lack selectivity. For some of these medications, the consequent immune suppression may predispose patients to serious opportunistic infections. An ideal therapy might target only those cells that are autoreactive, while maintaining the ability to discriminate and protect against foreign antigens and pathogens. Administration of anti-CD3 monoclonal antibody (referred to as anti-CD3) has been successfully used to induce immune tolerance. CD3 is the nonpolymorphic multisubunit protein complex associated with the antigenspecific T cell receptors (TCR) and is expressed on all CD4 and CD8 T cells. Intravenous anti-CD3 has been effective in animal models of autoimmunity and has shown promise in clinical trials of type 1 diabetes mellitus (Herold et al., 2002) and psoriatic arthritis, although side effects limit its chronic parenteral use. Exposure of the mucosal immune system to antigens can lead to development of distinct regulatory T cell subsets that maintain tolerance (Fig. 1). This physiological pathway has been exploited in animal models with oral anti-CD3 (Ochi et al., 2006; Ilan et al., 2010; Wu et al., 2010), which induces transforming growth factorbeta (TGF-b)-secreting T helper type 3 regulatory cells (Th3) that suppress autoimmune responses. In contrast, nasal anti-CD3 induces antiinflammatory interleukin-10 (IL-10)producing type 1 regulatory T cells (Tr1) (Wu et al., 2008, 2010). Both of these mucosal routes are well tolerated. Whether therapy that induces Tr1 cells might restore tolerance in progressive multiple sclerosis is unknown. In this issue of Brain, Mayo et al. provide compelling evidence for the induction of IL-10-producing Tr1like cells by nasal anti-CD3 antibody as a new therapeutic approach to treat progressive multiple sclerosis (Mayo et al., 2016). The influence of nasal anti-CD3 on chronic CNS inflammation and neurodegeneration was examined by these investigators using the nonobese diabetic (NOD) model of experimental autoimmune encephalomyelitis (EAE). In this model, induced by immunization with myelin oligodendrocyte glycoprotein (MOG), the early phase of EAE is self-limiting but is followed by an irreversible chronic progressive phase, making this an attractive model for progressive forms of multiple sclerosis. Nasal anti-CD3 suppressed both clinical and histopathological disease not only when given at the start of the progressive phase, but also when the progressive phase had been established. Nasal anti-CD3 administration in the progressive phase additionally stabilized blood–brain barrier integrity and promoted axonal protection. This treatment did not affect the ability to clear pulmonary bacterial infection, demonstrating that it was not globally immunosuppressive. Oral anti-CD3, which has proven effective in acute EAE models, had no effect in progressive EAE, providing further evidence that the two different routes of mucosal anti-CD3 administration employ distinct mechanisms. Indeed, flow cytometric analysis of peripheral lymphoid organs and CNS-infiltrating CD4 T cells revealed a profound increase in MOGspecific CD4 T cells that expressed IL-10. When isolated ex vivo, those IL-10-producing (IL-10 ) T cells suppressed T cell proliferation, Th17 polarization, and conferred tolerance when adoptively transferred in vivo. Interestingly, the T cells also expressed latency-associated peptide (LAP), a non-secreted precursor portion of TGF-b that is expressed on Th3 and Tr1 cells. However, the effects of nasal anti-CD3 were IL-10 dependent, as treatment with an IL-10 specific antibody reversed its clinical efficacy. Mayo et al. compared the transcriptional profile of nasal anti-CD3-induced IL-10 T cells to defined T cell subsets by microarray. The collection of genes (‘transcriptome’) expressed by nasal anti-CD3-induced IL-10 T cells was remarkably similar to the profile of Tr1 cells, but distinct from CD4CD25Foxp3 regulatory T BRAIN 2016: 139; 1866–1876 | 1866