Down-regulation of cell-surface CD4 co-receptor expression and modulation of experimental allergic encephalomyelitis

Fiori, P.; Ristori, Giovanni; Cacciani, Antonella; Buttinelli, Carla; Falcone, Marika; Giovanni, Simone Di; Montesperelli, C.; Pozzilli, Carlo; Salvetti, Marco

doi:10.1093/intimm/9.4.541

Cited by 11 publications

(6 citation statements)

References 3 publications

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“…Mechanistically, this was associated with down-regulated CD4 expression, which, to our knowledge, has not been reported in allogeneic tolerance induction. However, down-regulation of CD4 was previously reported in a rat model of experimental allergic encephalomyelitis (51). Similarly, down-regulation of CD8 has been observed as a mechanism for self-tolerance (52,53).…”

Section: Discussionmentioning

confidence: 87%

Differential Susceptibility of Allogeneic Targets to Indirect CD4 Immunity Generates Split Tolerance

Chan

Razavy

Anderson

2008

The Journal of Immunology

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CD4 T cells frequently help to activate CD8 T and B cells that effect transplant rejection. However, CD4 T cells alone can reject transplants, either directly or indirectly. The relative effectiveness of indirect CD4 immunity in rejecting different types of allogeneic grafts is unknown. To address this, we used a TCR transgenic mouse model in which indirect CD4 alloimmunity alone can be studied. We challenged transgenic recipients with hematopoietic cells and shortly thereafter skin transplants that could only be rejected indirectly, and observed Ag-specific indirect donor B cell and skin rejection, but not T cell elimination, reflecting a state of split tolerance. Deficiency of indirect CD4 alloimmunity in donor T cell rejection was also apparent when acute indirect rejection of donor islets occurred despite generation and maintenance of mixed T cell chimerism, due to migration of the few passenger T cells into recipient circulation. Although passenger lymphocytes delayed indirect islet rejection, they enhanced rejection by a full repertoire capable of both direct and indirect reactivity. Interestingly, the persistence of chimerism was associated with the eventual development of tolerance, as demonstrated by acceptance of donor skin grafts given late to hematopoietic cell recipients, and hyporesponsiveness of transgenic T cells from islet recipients in vitro. Mechanistically, tolerance was recessive and associated with progressive down-regulation of CD4. Collectively, our data indicate that indirect CD4 immunity is not equally destructive toward different types of allogeneic grafts, the deficiency of which generates split tolerance. The futility of these responses can convert immunity into tolerance.

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Section: Discussionmentioning

confidence: 87%

Differential Susceptibility of Allogeneic Targets to Indirect CD4 Immunity Generates Split Tolerance

Chan

Razavy

Anderson

2008

The Journal of Immunology

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“…Experimental studies on transgenic mice expressing the MBP T cell receptor indicate that the ability of the encephalitogenic clones to induce EAE is modulated by lymphocytes with different specificity, presumably specific for antigens present in the environment (9,10). Most of these studies have stressed the ability of immune responses to environmental antigens to activate the autoreactive T cells (30)(31)(32) and induce disease, but in a number of cases, it has been observed that responses against exogenous antigens can downregulate the encephalitogenic T cell clones (17)(18)(19)(20)(21). Several laboratories have reported that immunization with mycobacterial proteins such as PPD, hsp 65, and hsp 70 can confer protection against EAE, but the mechanisms responsible for this protection have not been elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…For example, it has been shown that the immune response against bacterial antigens can attenuate the outcome of experimental autoimmune diseases such as adjuvant arthritis, insulin-dependent diabetes mellitus in NOD mice, and EAE in mice and rats (12)(13)(14)(15)(16)(17)(18). In several studies, administration of mycobacterial proteins such as heat-shock cognate proteins of 65 and 70 kD, a 12-kD protein, or tuberculin PPD in IFA, induced protection against EAE (19)(20)(21). Understanding the mechanisms involved in the modulation of experimental autoimmune diseases could provide insights into immunologic strategies for developing useful interventions in human autoimmune diseases.…”

mentioning

confidence: 99%

A T Helper Cell 2 (Th2) Immune Response against Non-self Antigens Modifies the Cytokine Profile of Autoimmune T Cells and Protects against Experimental Allergic Encephalomyelitis

Falcone

Bloom

1997

The Journal of Experimental Medicine

125

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Experimental allergic encephalomyelitis (EAE) is an autoimmune disease of the central nervous system (CNS), and the most commonly used experimental model for multiple sclerosis. It is mediated by autoreactive T cell clones exhibiting a T helper cell (Th) 1 cytokine profile. Nonencephalitogenic T lymphocytes specific for self or exogenous antigens have been found to suppress encephalitogenic T cell responses and to protect against autoimmune disease. The mechanisms by which exogenous antigens modulate autoimmunity are not fully understood. In this study, we tested the hypothesis that a Th2-type immune response against an exogenous, nonself antigen, keyhole limpet hemocyanin (KLH), by releasing IL-4 in the microenvironment, could shift the cytokine profile of encephalitogenic T cells from an inflammatory Th1 to a protective Th2 type. SJL/J mice were preimmunized with the KLH in incomplete Freund's adjuvant to induce a population of Th2 memory cells that would be expected to release Th2 cytokines when activated by the specific antigen at the time of EAE induction. Four weeks later, mice received an encephalitogenic challenge containing guinea pig myelin in complete Freund's adjuvant with or without KLH. All KLH primed animals not receiving the exogenous antigen at the time of EAE induction developed a severe clinical disease indistinguishable from control mice not KLH primed. In contrast, animals preimmunized and challenged with the encephalitogenic inoculum containing KLH showed either no, or markedly reduced, clinical signs. Enzyme-linked immunospot analysis demonstrated that KLH-specific T cells in the primed mice were producing IL-4 characteristic of Th2 cells. In the KLH-primed and restimulated mice, the cytokine profile of the autoreactive, myelin basic protein–specific T cells was shifted from an inflammatory Th1 towards a protective Th2 type. We infer that the presence of IL-4 secreted by KLH-specific memory Th2 cells in the lymphoid system microenvironment in which the autoreactive T cells were engaged by the encephalitogenic stimulus were able to bias their cytokine profile towards a protective Th2 phenotype. This interpretation is supported by the observation that the protective effect of preimmunization with KLH was overcome by rm– IL-12, which inhibited the production of IL-4 by the Th1 cells and biased the autoimmune response to a predominantly Th1 type. Since IL-4 mRNA could not be detected by reverse transcriptase PCR in the CNS, the protective effect was inferred to be mediated by Th2 cells in the lymphoid system, and not the target organ. We conclude that exogenous, nonself antigens that can induce Th2 responses, can modify the cytokine environment sufficiently to alter the cytokine phenotype of inflammatory, autoreactive T cell clones, and ultimately, to provide significant protection against EAE and possibly other T cell–mediated autoimmune diseases.

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“…Other myelin Ag-specific EAE challenges have also been suppressed, supporting a role for bystander suppression in this model. Protection to EAE could also be achieved upon immunization with non-self Ags associated with down-regulation of CD4 coreceptor at the time of the EAE onset and/or EAE-specific immune deviation from Th1-to Th2-type by the change in the cytokine microenvironment in which encephalitogenic T cells developed (34,37). Collectively, these observations clearly provide a precedence for developing strategies for the treatment of autoimmune diseases using non-self Ags to induce bystander Th2 cell-mediated suppression.…”

Section: E Nterotoxigenic Escherichia Coli (Etec)mentioning

confidence: 99%

A Live Diarrheal Vaccine Imprints a Th2 Cell Bias and Acts as an Anti-Inflammatory Vaccine

Jun

Gilmore

Callis

et al. 2005

The Journal of Immunology

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An experimental vaccine for enterotoxigenic Escherichia coli (ETEC) composed of a live, attenuated Salmonella vector-expressing enterotoxigenic E. coli fimbriae, colonization factor Ag I (CFA/I), stimulated a biphasic Th cell response when given orally and suppressed the normally produced proinflammatory response. Such suppression was also evident upon the Salmonella-CFA/I infection of macrophages resulting in diminished TNF-α, IL-1, and IL-6 production and suggesting that the CFA/I fimbrial expression by Salmonella may protect against a proinflammatory disease. To test this hypothesis, SJL/J mice were vaccinated with Salmonella-CFA/I construct 1 or 4 wk before induction of experimental autoimmune encephalomyelitis using an encephalitogenic proteolipid protein peptide, PLP139–151. Mice receiving Salmonella-CFA/I vaccine recovered completely from mild acute clinical disease and showed only mild inflammatory infiltrates in the spinal cord white and gray matter. This protective effect was accompanied by a loss of encephalitogenic IFN-γ-secreting Th cells and was replaced with an increase in IL-4, IL-10, and IL-13 secretion. Collectively, these data suggested that Salmonella-CFA/I is an anti-inflammatory vaccine that down-regulates proinflammatory cells and confers protection against a proinflammatory disease, experimental autoimmune encephalomyelitis, via immune deviation.

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Down-regulation of cell-surface CD4 co-receptor expression and modulation of experimental allergic encephalomyelitis

Cited by 11 publications

References 3 publications

Differential Susceptibility of Allogeneic Targets to Indirect CD4 Immunity Generates Split Tolerance

Differential Susceptibility of Allogeneic Targets to Indirect CD4 Immunity Generates Split Tolerance

A T Helper Cell 2 (Th2) Immune Response against Non-self Antigens Modifies the Cytokine Profile of Autoimmune T Cells and Protects against Experimental Allergic Encephalomyelitis

A Live Diarrheal Vaccine Imprints a Th2 Cell Bias and Acts as an Anti-Inflammatory Vaccine

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