Different Therapeutic Outcomes in Experimental Allergic Encephalomyelitis Dependant Upon the Mode of Delivery of IL-10: A Comparison of the Effects of Protein, Adenoviral or Retroviral IL-10 Delivery into the Central Nervous System

Abstract

Experimental allergic encephalomyelitis (EAE) is a CNS autoimmune disease mediated by the action of CD4+ T cells, macrophages, and proinflammatory cytokines. IL-10 is a cytokine shown to have many anti-inflammatory properties. Studies have shown both inhibition and exacerbation of EAE after systemic IL-10 protein administration. We have compared the inhibitory effect in EAE of Il10 gene delivery in the CNS. Fibroblasts transduced with retroviral vectors expressing IL-10 could inhibit EAE. This was not associated with a prevention of cellular recruitment but an alteration in their phenotype, notably an increase in the numbers of CD8+ T and B cells. In marked contrast, CNS delivery of adenovirus coding for mouse IL-10 or IL-10 protein performed over a wide dose range failed to inhibit disease, despite producing similar or greater amounts of IL-10 protein. Thus the action of IL-10 may differ depending on the local cytokine microenvironment produced by the gene-secreting cell types.

Gene therapy in autoimmune, demyelinating disease of the central nervous system

“…46 Interestingly, an adenoviral mouse IL-10 (mIL-10) vector, albeit injected at lower titres, was clinically ineffective despite the production of CSF IL-10 levels that compared well with the levels produced by a retroviral cell vector (RCV-mIL-10) that inhibited the severity of clinical signs. 47 The level of infiltration generally correlates with the clinical severity of EAE. 68 Interestingly, in contrast to the prevention of leucocyte accumulation in the CNS that occurs in most other gene therapy studies, RCV-mIL-10-treated animals exhibited significant CNS infiltration but there was a dramatic shift in the phenotype of the infiltration.…”

“…Gene therapy has not yet been attempted in MS, but there have been a number of studies in EAE that have invariably shown some level of efficacy at inhibiting the disease (Table 1), although in many cases this has only been an amelioration rather than elimination of disease. As the majority of the CNS is postmitotic, this puts constraints on the nature of the vector that can be used, and to date administration of plasmid DNA, [32][33][34][35][36][37][38][39][40][41] viral infection, [42][43][44][45][46][47][48][49][50][51][52][53] and retrovirally transduced cell (RVC)-carriers 47,[54][55][56][57][58][59][60][61][62][63] have been investigated in EAE (Table 1). These have largely focused on inhibition of the immune response either applied centrally to target the local pathological events within the CNS or peripherally administered to inhibit: initial sensitization, the activities of circulating cells or perivascular events in areas of local BBB breakdown.…”

“…64 Where direct comparisons of delivery of inhibitory cytokine and cytokine inhibitory gene vectors have been made, central (CNS) administration exhibits greater efficacy than systemic delivery. 34,46,47,54 Importantly, the nature of the BBB limits not only influx but also importantly egress of molecules from the brain and can, depending on the dose injected, 43,46,47 create a local concentration gradient in the CNS that can achieve local therapy, but does not induce circulating levels that cause peripheral suppression of immune responses. 47,64 Therefore, the CNS may be a unique tissue to deliver potent immunosuppressive agents 43 (e.g.…”

“…64 Viral vectors can easily produce transgene levels in the range of 10-100 mg/ml within the CSF. 43,47,64 Expression of these vectors vary from a number of days (AV vectors), 43,46,47 to about a month (HSV-vectors), 64,67 which provides sufficient time to undertake experiments in EAE (Table 1). This compares well with the 10-100 ng/ml often produced for months Figure 1 Multiple disease processes occurring in EAE and MS. T cells (T) are expanded in peripheral lymphoid tissues and once activated they upregulate adhesion molecules (Eg CD49d), immunological receptors and migrate into tissues.…”

“…1 Gene therapy in demyelinating disease of CNS D Baker and DJR Hankey by retrovirally transduced cell vectors. 47,54 However, the level can be dose-titrated depending on the vector used, and the optimal levels for different cytokines are likely to be varied. Many of the immunological approaches used in gene therapy have evolved around the Th1/Th2 paradigm and IL-4 has been found most consistently to promote inhibition of EAE (Table 1).…”