Protection from experimental autoimmune encephalomyelitis (EAE): non-depleting anti-CD4 mAb treatment induces peripheral T-cell tolerance to MBP in PL/J mice

Biasi, Giovanni; Facchinetti, Antonella; Monastra, Giovanni; Mezzalira, Selene; Sivieri, S.; Tavolato, B.; Gallo, Paolo

doi:10.1016/s0165-5728(96)00188-9

Cited by 11 publications

(10 citation statements)

References 46 publications

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“…Therefore, and depending on the pathogen characteristics, active infection when anti-CD4 is administered may interfere with effective pathogen clearance. In fact, in the early 1990s there were some promising studies with anti-CD4-induced EAE protection (32,(44)(45)(46)) that led to some of the earliest clinical trials with therapeutic mAbs. However, the clinical development of this anti-CD4 therapy for MS was soon abandoned because of adverse effects related to CD4 T cell depletion (48).…”

Section: Discussionmentioning

confidence: 99%

“…Promising results in EAE following anti-CD4 treatment (32,(44)(45)(46) justified some of the earliest clinical trials of mAbs in MS in the early 1990s (47). However, the immaturity of the field at that time led to discouraging results, namely due to the immunogenicity of the mAb (it was not humanized) and to adverse effects due to T cell depletion (48).The mechanisms underlying the putative tolerogenic effect of anti-CD4 treatment in neuroinflammation were never fully characterized.…”

Section: Ultiple Sclerosis (Ms)mentioning

confidence: 99%

“…Previous studies primarily focused on the clinical amelioration afforded by CD4 mAb treatment on EAE in Biozzi AB/H (45), PL/J mice (44), and Lewis rats (32). Little is known regarding the underlying mechanisms.…”

Section: Nondepleting Anti-cd4 Mab Prevents Eaementioning

confidence: 99%

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T Cell Apoptosis and Induction of Foxp3+ Regulatory T Cells Underlie the Therapeutic Efficacy of CD4 Blockade in Experimental Autoimmune Encephalomyelitis

Duarte

Carrié

Oliveira

et al. 2012

The Journal of Immunology

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The pathogenesis of multiple sclerosis requires the participation of effector neuroantigen-specific T cells. Thus, T cell targeting has been proposed as a promising therapeutic strategy. However, the mechanism underlying effective disease prevention following T cell targeting remains incompletely known. We found, using several TCR-transgenic strains, that CD4 blockade is effective in preventing experimental autoimmune encephalopathy and in treating mice after the disease onset. The mechanism does not rely on direct T cell depletion, but the anti-CD4 mAb prevents the proliferation of naive neuroantigen-specific T cells, as well as acquisition of effector Th1 and Th17 phenotypes. Simultaneously, the mAb favors peripheral conversion of Foxp3+ regulatory T cells. Pre-existing effector cells, or neuroantigen-specific cells that undergo cell division despite the presence of anti-CD4, are committed to apoptosis. Therefore, protection from experimental autoimmune encephalopathy relies on a combination of dominant mechanisms grounded on regulatory T cell induction and recessive mechanisms based on apoptosis of neuropathogenic cells. We anticipate that the same mechanisms may be implicated in other T cell-mediated autoimmune diseases that can be treated or prevented with Abs targeting T cell molecules, such as CD4 or CD3.

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Section: Discussionmentioning

confidence: 99%

Section: Ultiple Sclerosis (Ms)mentioning

confidence: 99%

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T Cell Apoptosis and Induction of Foxp3+ Regulatory T Cells Underlie the Therapeutic Efficacy of CD4 Blockade in Experimental Autoimmune Encephalomyelitis

Duarte

Carrié

Oliveira

et al. 2012

The Journal of Immunology

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“…Therapeutic strategies in abrogating CD4+ T cell responses by either depletion of CD4+ T cells (Alters et al, 1990;Biasi et al, 1997) or by neutralization of chemokines conferred either protection or ameliorated severity of disease. Major pitfalls of anti-CD4 therapy were related to T cell depletion, while in general antibody based therapies face the challenge of the requirement for humanized antibodies to be successfully used for human therapy.…”

Section: Role Of Cd4+ T Cell Specific Chemoattractant Cytokine Il-16 mentioning

confidence: 99%

Experimental Models of Relapsing-Remitting Multiple Sclerosis: Current Concepts and Perspective

Skundric

2005

CNR

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Multiple sclerosis (MS) and its model experimental autoimmune encephalomyelitis (EAE) are debilitating paralytic diseases caused by inflammation, demyelination and axonal degeneration of the central nervous system (CNS). Whilst the autoimmune nature of MS is strongly suggested by evidence of myelin specific autoreactive T cells and antibodies, EAE is an experimentally induced CNS specific autoimmune disease. As opposed to the majority of MS patients, which exhibit a relapsing-remitting course of the disease, only a handful of available EAE models displays relapsingremitting course. In this review, we will summarize differences in regulation of acute and relapsing disease with emphasis on relapsing-remitting EAE models, and outline advantages and limitations of available relapsing EAE models pertinent for studies of relapsing human disease. We will discuss current concepts of relapse regulation by focusing on immune and molecular mechanisms of neuroinflammation, oligodendrocyte damage, myelin loss and axonal degeneration. This review will compare our present understanding of relapse regulation in human versus experimental autoimmune disease. Translation of mechanisms learned from relapsing EAE into development of new therapies for MS will be evaluated. Finally, perspectives in further optimization and development of more suitable experimental models to study human relapsingremitting MS will be discussed.

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“…In addition, it was found that clinical use of human chimeric anti-CD4 mAb did not inhibit activated CD4 + Th1 T cells in MS patients [29]. Other more promising studies with non-depleting anti-CD4 mAb have indicated potential efficacy in preclinical autoimmune [30,31] and transplantation models [32][33][34][35], and in clinical trials [36,37]. Although still unclear, the mechanism of tolerance induction by these mAb may be similar to the inhibitor activity found with TJU103, in disrupting the T cell activation process.…”

Section: Discussionmentioning

confidence: 99%

An Organic CD4 Inhibitor Reduces the Clinical and Pathological Symptoms of Acute Experimental Allergic Encephalomyelitis

Edling

Choksi

Huang

et al. 2002

Journal of Autoimmunity

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Protection from experimental autoimmune encephalomyelitis (EAE): non-depleting anti-CD4 mAb treatment induces peripheral T-cell tolerance to MBP in PL/J mice

Cited by 11 publications

References 46 publications

T Cell Apoptosis and Induction of Foxp3+ Regulatory T Cells Underlie the Therapeutic Efficacy of CD4 Blockade in Experimental Autoimmune Encephalomyelitis

T Cell Apoptosis and Induction of Foxp3+ Regulatory T Cells Underlie the Therapeutic Efficacy of CD4 Blockade in Experimental Autoimmune Encephalomyelitis

Experimental Models of Relapsing-Remitting Multiple Sclerosis: Current Concepts and Perspective

An Organic CD4 Inhibitor Reduces the Clinical and Pathological Symptoms of Acute Experimental Allergic Encephalomyelitis

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