Ofer Lider

Suppression of experimental autoimmune encephalomyelitis by oral administration of myelin basic protein: III. Synergistic effect of lipopolysaccharide☆

Oral administration of myelin basic protein (MBP) suppresses experimental autoimmune encephalomyelitis (EAE) in Lewis rats immunized with MBP in Freunds adjuvant. The immunomodulator bacterial lipopolysaccharide (LPS) when given orally in conjunction with MBP enhances the protective effects of MBP feeding in EAE. This synergy was achieved only following oral administration of LPS but not following subcutaneous injection. In contrast, subcutaneous administration of LPS abrogated oral tolerance. A synergism between oral LPS and MBP was also demonstrated for antigen-specific suppression of delayed type hypersensitivity (DTH) responses. Antibody responses to MBP were suppressed by oral administration of MBP but not by MBP plus LPS. The lipid A moeity of LPS mimicked the effects of LPS on disease protection and DTH suppression. These data demonstrate that adjuvants can enhance the induction of antigen-specific oral tolerance for suppression of cell-mediated experimental autoimmune responses.

Suppression of experimental autoimmune encephalomyelitis by oral administration of myelin basic protein. V. Hierarchy of suppression by myelin basic protein from different species

We have been investigating the suppression of experimental autoimmune encephalomyelitis (EAE) by oral tolerization to autoantigens. In the present study the tolerizing effect of orally administered myelin basic protein (MBP) from different species was examined in the Lewis rat, Hartley guinea pig, and SJL/J mouse model of EAE. Animals were fed guinea pig, rat, bovine, human or mouse-MBP and then immunized with the homologous species of MBP or myelin: Lewis rats were immunized with rat MBP, Hartley guinea pigs with guinea pig-MBP, and SJL/J mice with mouse myelin. Clinical expression of EAE and delayed-type hypersensitivity (DTH) responses to MBP were assessed. In each species, suppression of disease and DTH responses were most pronounced by tolerization with the homologous species of MBP. In addition, cross-species tolerization was observed in each species and in general was less suppressive than homologous MBP although in some instances MBP from a heterologous species was as effective as tolerization with the homologous species. We also studied guinea pig-MBP induced EAE in the Lewis rat because it is a widely studied model of EAE and found that oral tolerization with guinea pig MBP was as suppressive as rat MBP. Of note is that oral tolerization with mouse MBP suppressed myelin-induced EAE in the SJL mouse in which autoimmunity to proteolipid protein appears to play a primary role, suggesting that antigen-driven bystander suppression following oral tolerization with autoantigens (Miller et al., 1991b) may be an important contributing mechanism for suppression of EAE following oral tolerization with MBP in this model.(ABSTRACT TRUNCATED AT 250 WORDS)

Characterization of immunomodulatory properties and accessory cell function of small intestinal epithelial cells

We have studied the immunomodulatory properties of epithelial cells from the small intestine on T cell immune function in vitro. Proliferation of lymph node cells stimulated either with antigen or with mitogen was inhibited by epithelial cells in a dose-dependent fashion. The epithelial cell-mediated suppression of lymphocyte proliferation was blocked by indomethacin, a cyclooxygenase pathway inhibitor, demonstrating that the suppressive effect of epithelial cells was related to prostaglandin secretion. Furthermore, the action of epithelial cell-secreted prostaglandin on lymphocytes was related to its effect on IL-2 as the suppressive effect of epithelial cells was abrogated by the addition of exogenous IL-2. As previously reported, epithelial cells constitutively express MHC class II and we found them able to present antigen in a class II-restricted fashion when their suppressive effects were blocked by indomethacin. Furthermore, epithelial cells activated by LPS secrete an IL-1 like molecule in a fashion analogous to other antigen-presenting cells. These results demonstrate that epithelial cells can both enhance and suppress in vitro T cell immune responses and further characterize the mechanisms by which intestinal epithelial cells may function in gut-associated immune responses.

Suppression of Organ-Specific Autoimmune Diseases by Oral Administration of Autoantigens

One of the primary goals in developing effective therapy for autoimmune diseases is to specifically suppress autoreactive immune processes without affecting the remainder of the immune system. Autoimmune diseases involve the presence of autoreactive clones that have not been deleted in the thymus and thus these cells must be inactivated in the periphery. We have been investigating antigen-driven peripheral immune tolerance as a means to suppress autoimmune processes using the oral route of antigen-exposure to the immune system because of its inherent clinical applicability. An effective andlong-recognized method of inducing immunologic tolerance is the oral administration of antigen, which was first demonstrated by Wells for hen’s egg protein.[l] The mechanism by which orally administered antigen induces tolerance most probably relates to the interaction of protein antigens with gut-associatedlymphoid tissue (GALT) and the subsequent generationo? regulatory or suppressor T cells. [2] The two primary points of contact of orally administered antigen are Peyer’s patches and gut epithelial cells, thelatter of which overlie intraepitheliallymphocytes. Investigators have reported that specific suppressor cells can be found in the Peyer’s patches following oral administration of antigen and that such cells then migrate systemically.[2] Intestinal epithelial cells express class II antigens on their surface and thus have the capacity to function as antigen-presenting cells.[3] Furthermore, it has been shown that human gut epithelial cells preferentially stimulate CD8+ cells in vitro which can function to suppress in vitro immune responses. [4] Although most investigators have reported that the generation of antigen-specific suppressor T cells is the primary mechanism responsible for mediating oral tolerance, other reported mechanisms include anti-idiotypic antibodies, immune complexes and biologically filtered antigen (reviewed in REF. 5).

Induction of Hyperacute Brain Inflammation and Demyelination by Activated Encephalitogenic T Cells and a Monoclonal Antibody Specific for a Myelin/Oligodendrocyte Glycoprotein

CNS demyelinating inflammatory disease can be a multifactorial process mediated by cellular and antibody-mediated immune processes. Myelin basic protein (MBP)-specific T cells and pathogenic 8-18C5 antibody, specific for a myelin/oligodendrocyte glycoprotein (MOG), a minor component of CNS white matter, can coexist in rats without triggering disease. However, transfer of activated MBP-specific T-cells followed by the injection of 8-18C5 antibody resulted in hyperacute disease progression and CNS demyelination. Transfer of activated T cells specific for an irrelevant antigen or transfer of activated but irradiated encephalitogenic T cells did not induce disease in the presence of 8-18C5 antibody. When needle lesions were induced in brains of 8-18C5 antibody treated rats, no enhancement of demyelination was seen around the needle track. Thus, accessibility of the brain parenchyma to 8-18C5 antibody was not sufficient to induce local demyelination. Therefore, it appears that activated encephalitogenic T cells are involved in initiating the 8-18C5 antibody-mediated demyelinating process.