Limits...
Boosting regulatory T cell function by CD4 stimulation enters the clinic.

Becker C, Bopp T, Jonuleit H - Front Immunol (2012)

Bottom Line: Understanding tolerance mechanisms at the cellular and molecular level holds the promise to establish novel immune intervention therapies in patients with allergy or autoimmunity and to prevent transplant rejection.Administration of mAb against the CD4 molecule has been found to be exceptionally well suited for intentional tolerance induction in rodent and non-human primate models as well as in humanized mouse models.Recent evidence demonstrated that regulatory T cells (Treg) are directly activated by non-depleting CD4 ligands and suggests Treg activation as a central mechanism in anti-CD4-mediated tolerance induction.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.

ABSTRACT
Understanding tolerance mechanisms at the cellular and molecular level holds the promise to establish novel immune intervention therapies in patients with allergy or autoimmunity and to prevent transplant rejection. Administration of mAb against the CD4 molecule has been found to be exceptionally well suited for intentional tolerance induction in rodent and non-human primate models as well as in humanized mouse models. Recent evidence demonstrated that regulatory T cells (Treg) are directly activated by non-depleting CD4 ligands and suggests Treg activation as a central mechanism in anti-CD4-mediated tolerance induction. This review summarizes the current knowledge on the role of Treg in peripheral tolerance, addresses the putative mechanisms of Treg-mediated suppression and discusses the clinical potential of harnessing Treg suppressive activity through CD4 stimulation.

No MeSH data available.


Related in: MedlinePlus

Potential modes of tolerance induction by CD4-specific monoclonal antibodies.A short-term treatment with non-depleting CD4-specific mAb induces dominant tolerance to foreign proteins and transplanted allografts. This figure represents the different immune mechanisms that have been proposed to explain the tolerizing effect of CD4-specific mAb. Three intervening points can be distinguished: (A) CD4 binding by non-depleting CD4-specific mAb modulates antigenic stimulation through the T-cell receptor complex resulting in induction of T cell anergy. (B) By modulating antigenic stimulation, CD4-specific mAb induce differentiation of naive T cells into adaptive regulatory T cells, which control pathogenic effectors through transforming growth factor-β (TGF-β) and IL-10 release. (C) Crucially important for tolerance induction, CD4-specific mAb activate the (cAMP-dependent) suppressive function of Treg, which, upon activation, exert control on pathogenic T cells by direct and linked suppression.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC3376463&req=5

Figure 1: Potential modes of tolerance induction by CD4-specific monoclonal antibodies.A short-term treatment with non-depleting CD4-specific mAb induces dominant tolerance to foreign proteins and transplanted allografts. This figure represents the different immune mechanisms that have been proposed to explain the tolerizing effect of CD4-specific mAb. Three intervening points can be distinguished: (A) CD4 binding by non-depleting CD4-specific mAb modulates antigenic stimulation through the T-cell receptor complex resulting in induction of T cell anergy. (B) By modulating antigenic stimulation, CD4-specific mAb induce differentiation of naive T cells into adaptive regulatory T cells, which control pathogenic effectors through transforming growth factor-β (TGF-β) and IL-10 release. (C) Crucially important for tolerance induction, CD4-specific mAb activate the (cAMP-dependent) suppressive function of Treg, which, upon activation, exert control on pathogenic T cells by direct and linked suppression.

Mentions: As summarized in Figure 1 at least three different immune mechanisms can be distinguished that help to explain the tolerizing effect of CD4-specific agents: First, a general Treg-independent mechanism that consist in interference with proper CD4 coreceptor function resulting in induction of T cell anergy or T cell depletion (Figure 1A). This effect seems to depend either on CD4/MHC class II binding blockade or additional TCR-independent signaling. Second, by modulating antigenic stimulation, individual CD4 mAb induce differentiation of naive T cells into adaptive Tregs (Oliveira et al., 2008), which are suggested to control pathogenic effectors through TGF-β (Oliveira et al., 2011) or IL-10 release (Figure 1B). Finally, and crucially important for tolerance induction, CD4-specific mAb activate the suppressive function of Treg (Becker et al., 2007; Kendal et al., 2011), which, upon activation, exert control on pathogenic T cells by direct and linked suppression (Figure 1C). These different effects of CD4 stimulation are intrinsic functions of individual anti-CD4 mAb.


Boosting regulatory T cell function by CD4 stimulation enters the clinic.

Becker C, Bopp T, Jonuleit H - Front Immunol (2012)

Potential modes of tolerance induction by CD4-specific monoclonal antibodies.A short-term treatment with non-depleting CD4-specific mAb induces dominant tolerance to foreign proteins and transplanted allografts. This figure represents the different immune mechanisms that have been proposed to explain the tolerizing effect of CD4-specific mAb. Three intervening points can be distinguished: (A) CD4 binding by non-depleting CD4-specific mAb modulates antigenic stimulation through the T-cell receptor complex resulting in induction of T cell anergy. (B) By modulating antigenic stimulation, CD4-specific mAb induce differentiation of naive T cells into adaptive regulatory T cells, which control pathogenic effectors through transforming growth factor-β (TGF-β) and IL-10 release. (C) Crucially important for tolerance induction, CD4-specific mAb activate the (cAMP-dependent) suppressive function of Treg, which, upon activation, exert control on pathogenic T cells by direct and linked suppression.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3376463&req=5

Figure 1: Potential modes of tolerance induction by CD4-specific monoclonal antibodies.A short-term treatment with non-depleting CD4-specific mAb induces dominant tolerance to foreign proteins and transplanted allografts. This figure represents the different immune mechanisms that have been proposed to explain the tolerizing effect of CD4-specific mAb. Three intervening points can be distinguished: (A) CD4 binding by non-depleting CD4-specific mAb modulates antigenic stimulation through the T-cell receptor complex resulting in induction of T cell anergy. (B) By modulating antigenic stimulation, CD4-specific mAb induce differentiation of naive T cells into adaptive regulatory T cells, which control pathogenic effectors through transforming growth factor-β (TGF-β) and IL-10 release. (C) Crucially important for tolerance induction, CD4-specific mAb activate the (cAMP-dependent) suppressive function of Treg, which, upon activation, exert control on pathogenic T cells by direct and linked suppression.
Mentions: As summarized in Figure 1 at least three different immune mechanisms can be distinguished that help to explain the tolerizing effect of CD4-specific agents: First, a general Treg-independent mechanism that consist in interference with proper CD4 coreceptor function resulting in induction of T cell anergy or T cell depletion (Figure 1A). This effect seems to depend either on CD4/MHC class II binding blockade or additional TCR-independent signaling. Second, by modulating antigenic stimulation, individual CD4 mAb induce differentiation of naive T cells into adaptive Tregs (Oliveira et al., 2008), which are suggested to control pathogenic effectors through TGF-β (Oliveira et al., 2011) or IL-10 release (Figure 1B). Finally, and crucially important for tolerance induction, CD4-specific mAb activate the suppressive function of Treg (Becker et al., 2007; Kendal et al., 2011), which, upon activation, exert control on pathogenic T cells by direct and linked suppression (Figure 1C). These different effects of CD4 stimulation are intrinsic functions of individual anti-CD4 mAb.

Bottom Line: Understanding tolerance mechanisms at the cellular and molecular level holds the promise to establish novel immune intervention therapies in patients with allergy or autoimmunity and to prevent transplant rejection.Administration of mAb against the CD4 molecule has been found to be exceptionally well suited for intentional tolerance induction in rodent and non-human primate models as well as in humanized mouse models.Recent evidence demonstrated that regulatory T cells (Treg) are directly activated by non-depleting CD4 ligands and suggests Treg activation as a central mechanism in anti-CD4-mediated tolerance induction.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.

ABSTRACT
Understanding tolerance mechanisms at the cellular and molecular level holds the promise to establish novel immune intervention therapies in patients with allergy or autoimmunity and to prevent transplant rejection. Administration of mAb against the CD4 molecule has been found to be exceptionally well suited for intentional tolerance induction in rodent and non-human primate models as well as in humanized mouse models. Recent evidence demonstrated that regulatory T cells (Treg) are directly activated by non-depleting CD4 ligands and suggests Treg activation as a central mechanism in anti-CD4-mediated tolerance induction. This review summarizes the current knowledge on the role of Treg in peripheral tolerance, addresses the putative mechanisms of Treg-mediated suppression and discusses the clinical potential of harnessing Treg suppressive activity through CD4 stimulation.

No MeSH data available.


Related in: MedlinePlus