Immune Modulation And Increased Neurotrophic Factor Production In Multiple Sclerosis Patients Treated With Testosterone

Stefan M. Gold; Sara Chalifoux; Barbara S. Giesser; Rhonda R. Voskuhl

Disclosures

J Neuroinflammation 

In This Article

Abstract and Background

Abstract

Background: Multiple sclerosis is a chronic inflammatory disease of the central nervous system with a pronounced neurodegenerative component. It has been suggested that novel treatment options are needed that target both aspects of the disease. Evidence from basic and clinical studies suggests that testosterone has an immunomodulatory as well as a potential neuroprotective effect that could be beneficial in MS.
Methods: Ten male MS patients were treated with 10 g of gel containing 100 mg of testosterone in a cross-over design (6 month observation period followed by 12 months of treatment). Blood samples were obtained at three-month intervals during the observation and the treatment period. Isolated blood peripheral mononuclear cells (PBMCs) were used to examine lymphocyte subpopulation composition by flow cytometry and ex vivo protein production of cytokines (IL-2, IFNγ, TNFα, IL-17, IL-10, IL-12p40, TGFβ1) and growth factors (brain-derived neurotrophic factor BDNF, platelet-derived growth factor PDGF-BB, nerve growth factor NGF, and ciliary neurotrophic factor CNTF). Delayed type hypersensitivity (DTH) skin recall tests were obtained before and during treatment as an in vivo functional immune measure.
Results: Testosterone treatment significantly reduced DTH recall responses and induced a shift in peripheral lymphocyte composition by decreasing CD4+ T cell percentage and increasing NK cells. In addition, PBMC production of IL-2 was significantly decreased while TGFβ1 production was increased. Furthermore, PBMCs obtained during the treatment period produced significantly more BDNF and PDGF-BB.
Conclusion: These results are consistent with an immunomodulatory effect of testosterone treatment in MS. In addition, increased production of BDNF and PDGF-BB suggests a potential neuroprotective effect.

Background

Multiple sclerosis (MS) has been considered a putative T cell mediated autoimmune disease. However, it is becoming increasingly clear that its pathology is far more complicated and is characterized by both an inflammatory component as well as a neurodegenerative process.[1] To date, the relationship between inflammation and the neurodegeneration in MS is unclear. Nevertheless, it is currently thought that potential new treatments should ideally have anti-inflammatory as well as neuroprotective properties.[2]

Numerous models of autoimmune diseases including experimental autoimmune encephalomyelitis (EAE), diabetes in nonobese mice, thyroiditis, and adjuvant arthritis have been shown to be worsened by castration of male animals.[3,4,5,6,7,8] Furthermore, testosterone treatment ameliorates EAE.[9] These protective effects are thought to be mediated by testosterone's immunomodulatory properties such as decreasing the production of pro-inflammatory cytokines TNFα and IL-1β by macrophages[10] and monocytes[11] as well as increasing production of the anti-inflammatory cytokine IL-10 by T cells.[12]

In addition, evidence supporting a neuroprotective effect of testosterone has been found in a variety of neurological diseases as well as in the cognitive decline associated with normal aging.[13] Testosterone is converted to estrogen in the brain by aromatase, and the neuroprotective properties of testosterone treatment in vivo may be due at least in part to this conversion. However, several in vitro studies have shown that testosterone can also be more directly neuroprotective.[14] Testosterone has been shown to protect spinal cord neurons in culture from glutamate-mediated toxicity, as well as to induce neuronal differentiation and increase neurite outgrowth.[15] Testosterone treatment also protected cultured neurons against beta-amyloid toxicity induced cell death.[16]

While CNS infiltrating immune cells were once thought to always be deleterious, it has since been established that they have the potential to be beneficial under certain conditions, since neurotrophic factors have been detected in peripheral blood mononuclear cells (PBMCs).[17] Indeed, production of the neurotrophic factors BDNF and NT-3 by immune cells has been shown to accompany better recovery from spinal cord injury,[18] and the production of neurotrophic factors by immune cells has been hypothesized as a potential means of neuroprotection in MS.[19]

Recently, a pilot clinical trial using testosterone to treat 10 male MS patients was completed.[20] In these patients, cognitive function improved and the brain atrophy rate was significantly slowed. Here, immunomodulatory effects of testosterone treatment as well as its ability to induce neurotrophic growth factor production in PBMCs were examined in these patients to explore a potential novel pathway underlying testosterone's beneficial effects.

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