Experimental autoimmune encephalomyelitis (EAE) is still the most widely accepted animal model of multiple sclerosis (MS). Different types of EAE have been developed in order to investigate pathogenetic, clinical and therapeutic aspects of the heterogenic human disease. Generally, investigations in EAE are more suitable for the analysis of immunogenetic elements (major histocompatibility complex restriction and candidate risk genes) and for the study of histopathological features (inflammation, demyelination and degeneration) of the disease than for screening of new treatments. Recent studies in new EAE models, especially in transgenic ones, have in connection with new analytical techniques such as microarray assays provided a deeper insight into the pathogenic cellular and molecular mechanisms of EAE and potentially of MS. For example, it was possible to better delineate the role of soluble pro-inflammatory (tumor necrosis factor-α, interferon-γ and interleukins 1, 12 and 23), anti-inflammatory (transforming growth factor-β and interleukins 4, 10, 27 and 35) and neurotrophic factors (ciliary neurotrophic factor and brain-derived neurotrophic factor). Also, the regulatory and effector functions of distinct immune cell subpopulations such as CD4+ Th1, Th2, Th3 and Th17 cells, CD4+FoxP3+ Treg cells, CD8+ Tc1 and Tc2, B cells and γδ+ T cells have been disclosed in more detail. The new insights may help to identify novel targets for the treatment of MS. However, translation of the experimental results into the clinical practice requires prudence and great caution.

Various types of experimental autoimmune encephalomyelitis (EAE) reflect some of the pathogenetic, clinical, and therapeutic features of the different forms of multiple sclerosis (MS), thereby, providing some, albeit limited, insight into the molecular and cellular basis of the human disease. Specific questions of MS therapy including the search for new therapeutic targets and strategies and their validation require investigations in different available EAE models. A survey is given of experimental therapeutic approaches that are currently under study with the most promising examples of monoclonal antibodies, gene therapy, stem cell transplantation and orally applied small molecular weight disease-modifying drugs. Reasons for therapy failure and adverse side-effects of some experimental trials are discussed. Precaution is advised, if results of new experimental approaches are translated into clinical practice.

Three groups of patients suffering from acute attacks or progressive multiple sclerosis (MS) are under investigation. First results revealed remarkable clinical improvements of patients with acute attacks in the groups treated by therapeutic plasma exchange (TPE) and immunoadsorption (IA). Only slight or no improvements were seen in the patients of the control group treated only with steroids. Plasma protein levels (IgG, IgM, IgA, fibrinogen) were considerably reduced in patients of the TPE group after each treatment procedure as expected. The same holds true concerning the total hemolytic capacities (THC) of the complement of the classic (CP) and the alternative (AP) pathway. On the other hand in the IA group only slight decreases of plasma proteins (about 20%) were observed, but the behaviour of THC's were quite similar than those seen in the patients of the TPE group. The THC decreases in both groups can be explained by removal of all complement factors (TPE group) or by the adsorption of single factors (IA group) of both complement pathways according to earlier in vitro investigations. The THC decreases in patients of both groups suffering from acute MS attacks could mean an "antiinflammatory" effect and could--at least partially--contribute to the clinical improvements of these patients.

For diseases of unknown aetiology, the question as to whether the incidence is constant or variable is very important. A study on multiple sclerosis in a defined northern area of the German Democratic Republic showed a prevalence of 68.6 and an incidence rate of 3.0. Retrospective and prospective investigations concerning an observation period of 22 years revealed cyclic periods (6-7 years) of high incidence rates (up to 4.5) interrupted by shorter intervals (4-5 years) with low rates (about 1.8). The differences (1963-1968 vs. 1969-1973, 1974-1978 vs. 1979-1983) are significant. In accordance with the findings of Kurtzke et al. on a cyclic outbreak of multiple sclerosis in the Faroes and Iceland, our results are considered to be a consequence of environmental factors, such as epidemic viral infections.

At present, the most efficient therapeutical treatment of multiple sclerosis (MS) is achieved by IFN-beta. However, its in vivo effects remain incompletely understood. If applied parenterally, the hydrophobic IFN-beta acts primarily on blood cells with probable selectivity for functionally different lymphocyte subpopulations, monocytes and granulocytes. We have investigated the expression of the activation marker interleukin-2 receptor-alpha (CD25) on CD3+ T cells, CD19+ B cells, foetal-type gamma(delta)+CD3+ T cells and foetal-type CD5+CD19+ B cells of the peripheral blood. In addition, the oxidative burst activity and apoptosis have been determined in mononuclear and polymorphonuclear blood cells, respectively. The study accompanied a phase III trial with IFN-beta1b (BETAFERON, Schering). Two groups of MS patients with relapsing-remitting course of the disease have been investigated at 8 time points (days 0, 5, 15, 31, 60, 90, 180 and 270 after starting therapy): (1) verum group (n = 8) with application of 8 Mill. units IFN-beta1 b every other day, and (2) placebo group (n = 4) with application of placebo for 3 months and therapy as in (1) from day 90 onward. The main results were: (1) Activated T cells decreased until day 180 in the verum group and return thereafter to pre-treatment values, whereas in the placebo group the values remained relatively stable over the whole observation period. (2) Activated B cells increased between days 90 and 270 in both groups, i.e. after verum application in both groups. (3) Foetal-type B cells were more activated than total B and T cells with increase over time in both groups. (4) Foetal-type T cells exerted relatively stable intra-individual levels with generally low CD25 expression, but punctual CD25 peaks in both groups. (5) The spontaneous oxidative burst was higher in lymphocytes, more variable in monocytes and faster increasing in granulocytes in the verum group than in the placebo group. (6) Apoptosis of mononuclear cells and granulocytes showed similar variations in the verum and placebo groups with the exception of a selective increase over time of the proportion of granulocytes undergoing induced apoptosis in the verum group. It is concluded that IFN-beta has the following main effects on the immune system of MS patients: (1) the T cell immunity is systemically and reversibly suppressed, (2) the foetal-type lymphocytes, which are responsible for the first line of defence of infections, are stimulated in the long range, (3) the oxidative burst activity is increased in lymphocytes and granulocytes and instable in monocytes, and (4) the inducibility of apoptosis in granulocytes is increased. Re-examination of the altered blood cell parameters after long-term IFN-beta therapy is warranted.