Delivery of myelin peptides through the first line of defense, skin, to counter autoimmunity in multiple sclerosis

Military metaphors provide a convenient way to help understand the powerful and exciting new therapies for relapsing remitting multiple sclerosis (RRMS). In fact, military language is highly relevant for describing the immune system, our physiological defense force that when functioning normally protects us from harmful microbes and engages in surveillance against malignancies. A key first line of immune defense is our skin. In this month’s Annals, Jurynczyk and colleagues show how that key defense line can be used to help regulate an aberrant immune response in multiple sclerosis (MS). One of the main characteristics of MS pathology is the immune system’s ‘‘friendly fire,’’ which mistakenly targets self-antigens, in this case myelin. The transdermal delivery of myelin peptides was shown to induce immune tolerance regulation or tolerance, in order to achieve a ‘‘cease fire’’ in those immune responses to myelin seen in MS. Such an approach stands in stark contrast to the types of strategies seen these days in many successful phase 2 and phase 3 trials in RRMS. Most of these trials involve administration of a molecule that inhibits a major immune function and often eliminates a wide swath of immune cells. Such strong weapons frequently make the individual with MS who is under treatment, lymphopenic, or even severely depleted in 1 or more of the major immune cell populations. Perhaps a more sensible approach is contained within the tactics employed by Jurynczyk and colleagues, in which the investigators attempted to induce regulatory control of autoimmunity without major impairment of the normal functions of the immune system. Current approaches that show greatest promise for treating the inflammation associated with MS use heavy weaponry: For example, Rituximab and Alemtuzumab, two monoclonal antibodies that reduce relapse rate, were first developed and approved for their activities in combating lymphoid malignancies. These monoclonal antibodies deplete critical components of the immune system. Rituximab, which depletes CD20 B cells, is approved for treatment of B cell lymphoma, while Alemtuzumab depletes cells bearing CD52, found on T cells, B cells, and other monocytoid cells and is approved for chronic lymphocytic leukemia. Another small-molecule drug, Cladribine, a purine analog used for hairy cell leukemia that kills T cells and B cells, also reduces MS relapse rate and is being reviewed by the U.S. Food and Drug Administration (FDA) for approval. One needs T cells and B cells for normal immune function. The metaphor of ‘‘heavy weaponry’’ can be applied to most of today’s experimental drugs for RRMS, as well as to an approved therapeutic. For example, Natalizumab blocks lymphocyte migration into the brain, while Fingolimod inhibits lymphocyte egress from regional lymph nodes. Both drugs exemplify a strategy to interdict the movement of immune cells to the target in the central nervous system. Natalizumab blocks lymphocyte homing to the brain via blockade of a4 integrin, while Fingolimod blocks lymphocyte egress from lymph nodes by targeting the sphingosine phosphate 1 receptor. Lymphocytes, in order to guard against infection, must have the capabilities of a mobile force, so they can patrol distant tissues like the brain. Mobility and surveillance is key for protection against dormant viruses in the brain that reside in the central nervous system. While inhibition of homing to brain may be beneficial for reducing inflammation inside the brain, there is a real risk that inhibition of surveillance will lead to opportunistic infections. Of course this has been seen most dramatically in the case of Natalizumab, in which prolonged use beyond 2 years is associated with rates of progressive multifocal leukoencephalopathy (PML) approaching 1 in 500. In contrast to these ‘‘big guns,’’ which aim to impair wide swaths of the immune system, the induction of antigenspecific tolerance or regulation has not received much attention for treatment of RRMS. In this month’s Annals, Jurynczyk and colleagues have attempted to induce a form of regulation that would target only a small part of the immune system: those cells directed to making autoimmune responses to components of the myelin sheath. The success of this approach, whereby self-antigens are delivered transdermally to induce immune tolerance, would amount to the