INCREASED TRANSFORMING GROWTH-FACTOR-BETA, INTERLEUKIN-4, AND INTERFERON-GAMMA IN MULTIPLE-SCLEROSIS

The inflammatory nature of multiple sclerosis (MS) implicates the part icipation of immunoregulatory cytokines, including the T-helper type 1 (Th1) cell-associated interferon-gamma (IFN-gamma), the Th2 cell-rela ted interleukin-4 (IL-4), and the immune response-downregulating cytok ine transforming growth factor-beta (TGF-beta), but proof for their in volvement in MS has been lacking. By adopting in situ hybridization wi th complementary DNA oligonucleotide probes for human IFN-gamma IL-4, and TGF-beta, the expression of mRNA for these cytokines was detected in mononuclear cells (MNC) from blood and cerebrospinal fluids. Strong ly elevated levels of MNC expressing all three cytokines were found in peripheral blood and at even higher frequencies in cerebrospinal flui d from untreated patients with MS and optic neuritis, i.e., a common f irst manifestation of MS, compared with patients with other neurologic al diseases and healthy subjects. In MS and optic neuritis, IL-4 mRNA expressing cells predominated, followed by TGF-beta- and IFN-gamma-pos itive cells. Control patients with myasthenia gravis had similarly ele vated levels of IFN-gamma and TGF-beta mRNA expressing blood MNC but l ower numbers of IL-4-positive cells. No or slight disability of MS was associated with high levels of TGF-beta mRNA expressing tells, while MS patients with moderate or severe disability had high levels of IFN- gamma-positive cells. IFN-gamma and TGF-beta may have opposing effects in MS, and treatments inhibiting IFN-gamma and/or promoting TGF-beta might ameliorate MS.