Neuropeptide Regulation of Immunity: The Immunosuppressive Activity of Alpha‐Melanocyte‐Stimulating Hormone (α‐MSH)

Abstract

A BSTRACT : The ocular microenvironment is an extreme example of regional immunity. Within its microenvironment, expression of delayed type hypersensitivity (DTH) is suppressed. This immunosuppression is mediated in part by the constitutive expression of ␣ -MSH. Previously we have found that ␣ -MSH suppresses the production of IFN-␥ by activated effector T cells. Recently we have found that ␣ -MSH can mediate induction of TGF-␤ -producing T cells that act as regulatory T cells. This has encouraged us to further examine the potential for ␣ -MSH to suppress T cell-mediated inflammation (autoimmune disease) and to regulate lymphokine production by effector T cells. When ␣ -MSH was injected i.v. into mice at the time of peak retinal inflammation, the severity of experimental autoimmune uveitis (EAU) was significantly suppressed. Effector T cells activated in vitro in the presence of ␣ -MSH proliferated and produced IL-4 and enhanced levels of TGF-␤ while their IFN-␥ and IL-10 production was suppressed. The ␣ -MSH-treated T cells functioned as regulatory T cells by suppressing in vitro IFN-␥ production by other inflammatory T cells. This regulatory activity was the function of ␣ -MSH-treated CD4 + CD25 + T cells. Therefore, ␣ -MSH mediates immunosuppression by inducing a differential expression of lymphokine production and by inducing activation of regulatory functions in T cells. This implies that ␣ -MSH may take part in regional mechanisms of immunosuppression and possibly peripheral tolerance. Thus, ␣ -MSH can be used to suppress autoimmune disease and possibly reestablish tolerance to autoantigens.

The diminishment of experimental autoimmune encephalomyelitis (EAE) by neuropeptide alpha-melanocyte stimulating hormone (α-MSH) therapy

“…Using a treatment procedure we used to diminish EAU in mice (Taylor et al, 2000), we found that this similar procedure diminished the severity of EAE in mice. We adapted the role of α-MSH in immune privilege to treat another T cell mediated autoimmune disease.…”

“…Others have shown that a single systemic injection of α-MSH at the time of an acute phase response induced by endotoxin suppressed the inflammation in the infected tissue site and returned body temperature to normal (Glyn and Lipton, 1981;Martin and Lipton, 1990;Villar et al, 1991). When we made a similar systemic injection of α-MSH in mice with EAU there was an accelerated resolution of ocular inflammation (Taylor et al, 2000). Recently we have found that α-MSH may have an important role in the natural recovery of mice from EAU by promoting induction of retinal autoantigen-specific Treg cells that we find in the post-EAU spleen, and in minimizing retinal tissue damage during an episode of uveitis (Kitaichi et al, 2005).…”

“…Therapeutic α-MSH-treatments have been tried in animal models of septic shock, contact dermatitis, rheumatoid arthritis, acute pancreatitis, toxin-induced liver failure, allergic airway inflammation, endotoxin induce uveitis, and experimental autoimmune uveoretinitis (Ceriani et al, 1994;Grabbe et al, 1996;Jahovic et al, 2004;Martin and Lipton, 1990;Nishida et al, 2004;Raap et al, 2003;Shiratori et al, 2004;Taylor et al, 2000;Wang et al, 2004). In addition, two other groups of researchers have attempted to use different forms of gene therapy to see if delivering α-MSH into the immune response of EAE will suppress the onset and subsequent pathology of EAE.…”

Inducible immune regulation following autoimmune disease in the immune-privileged eye

“…The severity of retinal inflammation was clinically assessed every 3 or 4 days by fundus examination and scored on a 0 -5 scale [24,25,33]. Eyes were given a score of 0 for no inflammation; eyes with only white focal lesions of vessels were given a scored of 1; eyes with linear vessel lesions, over less than half of the retina, were given a scored of 2; eyes with linear vessels lesions, over more than half of the retina, were given a score of 3; eyes with severe chorioretinal exudates or retinal hemorrhages in addition to the vasculitis were given a score of 4; and eyes with a subretinal hemorrhage or a retinal detachment were given a score of 5.…”

Endogenous Cortisol and TGF-β in Human Aqueous Humor Contribute to Ocular Immune Privilege by Regulating Dendritic Cell Function

“…In vivo and in vitro animal studies have suggested that TGF-b2 (8,9) and a-melanocyte-stimulating hormone (a-MSH) (10,11) are the dominant immunosuppressive molecules in AqH, with well-documented inhibitory effects on macrophage inflammatory activity and on the generation of Th1 responses. Because almost all functional studies have used either rabbit AqH (10,(12)(13)(14)(15)(16)(17)(18) or murine AqH (18,19), it is unclear to what extent these molecules are involved in APC regulation in humans, or whether other mechanisms such as endogenous glucocorticoids, notably cortisol (20,21), play a role.…”