Oral tolerance to myelin basic protein and natural recovery from experimental autoimmune encephalomyelitis are associated with downregulation of inflammatory cytokines and differential upregulation of transforming growth factor beta, interleukin 4, and prostaglandin E expression in the brain.

Abstract

SummaryExperimental autoimmune encephalomyelitis (EAE) in the Lewis rat is a self-limited inflammatory process localized to the central nervous system that is induced by the injection of myelin basic protein (MBP) in adjuvant . Oral administration of MBP suppresses EAE, and this suppression is mediated by CD8+ T cells that adoptively transfer protection and suppress both in vitro and in vivo by the release of transforming growth factor (TGF) (3 after antigen-specific triggering. Furthermore, oral tolerance to MBP is enhanced by the concomitant oral administration of lipopolysaccharide (LPS) . The present study was undertaken to determine whether the disease course in EAE and its suppression by oral tolerization to MBP is associated with distinct patterns of cytokine expression in the target organ . Detailed immunohistology of the brain was performed at the peak of clinical disease (day 14 after immunization) and after recovery (day 18) in control (ovalbumin [OVA]-fed), MBP-fed, and MBP plus LPS-fed animals . Brains from OVA-fed animals at the peak of disease showed perivascular infiltration with activated mononuclear cells which secreted the inflammatory cytokines interleukins (IL) 1, 2, 6, 8, TNF-a, and interferon 'y. The inhibitory cytokines TGF-0 and IL4, and prostaglandin E2 (PGE2) were absent. In MBP orally tolerized animals there was a marked reduction of the perivascular infiltrate and downregulation of all inflammatory cytokines. In addition, there was upregulation of the inhibitory cytokine TGF-,(3 . In MBP plus LPS orally tolerized animals, in addition to upregulation of TGF-0 and reduction of inflammatory cytokines, there was enhanced expression of IL-4 and PGE2, presumably secondary to activation of an additional population of immunoregulatory cells. In OVA-fed animals that had recovered (day 18), staining for inflammatory cytokines diminished, and there was the appearance of TGF-0 and IL-4. These results suggest that suppression of EAE, either induced by oral tolerization or that which occurs during natural recovery is related to the secretion of inhibitory cytokines or factors that actively suppress the inflammatory process in the target organ .

Active suppression in orally tolerized rats coincides within situtransforming growth factor-beta (TGF-β) expression in the draining lymph nodes

“…In conclusion, our findings are in agreement with other studies, where TGF-b has been found to mediate the active suppression responsible for oral tolerance [15][16][17][18]. However, this is the first time TGF-b production has been demonstrated in situ, in response to parenteral challenge with a previously orally given heterologous antigen.…”

“…Many studies suggest that TGF-b may be the key cytokine that mediates active suppression [7,16,17], but to our knowledge it has only once been shown that TGF-b is being produced in vivo in nontransgenic animals-in response to an orally given autologous antigen in the rat experimental autoimmune encephalitis model [18]. Therefore, we decided to investigate the presence of TGF-b in situ in our system, where we have observed a suppressed inflammatory response of the draining lymph node, due to the presence of a heterologous antigen to which the animal previously had been orally tolerized.…”

Augmentation of natural immunity to a pro-inflammatory cytokine (TNF-alpha) by targeted DNA vaccine confers long-lasting resistance to experimental autoimmune encephalomyelitis

“…22,23,[30][31][32][68][69][70][71][72] The current study demonstrates, for the first time, the appearance of 'natural' antiself antibodies to a key pro-inflammatory cytokine, TNF-␣, during the development of a T cell-mediated autoimmune disease of the CNS. These antibodies developed in rats immunized with p68-86/CFA and not with the CFA alone (Figure 3), even though both groups exhibited an extensive local inflammatory process at the site of CFA immunization.…”

“…This type of control has been termed peripheral tolerance. T cell anergy, 69 active suppression, 31,[68][69][70] T cell deletion 93,94 and generation of anti-idiotypic immunity 95 have been described as key mechanisms that contribute to the maintenance of peripheral tolerance. The current study suggests, for the first time, that self-specific T and B cells, capable of mounting self-specific immunity against pro-inflammatory mediators, escape central tolerance to provide the immune system with a powerful tool with which it keeps its dangerous anti-self activity under control and thus maintains tolerance to self in the periphery.…”

The application of gene therapy in autoimmune diseases

“…[8][9][10] This may represent restoration of a more balanced immune response to auto-antigen stimulation and result in disease amelioration. Although alteration of effector function of a differentiated CD4 + T cell appears to be unlikely, 11,12 it appears to be possible to modulate the effector function and differentiation of undifferentiated Th0 T cells and CD4 + T cells that are not completely differentiated.…”