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Regulatory T Cells: Serious Contenders in the Promise for Immunological Tolerance in Transplantation.

Safinia N, Scotta C, Vaikunthanathan T, Lechler RI, Lombardi G - Front Immunol (2015)

Bottom Line: The relevance of Treg migratory capacity will also be discussed together with methods of in vivo visualization of the infused cells.Moreover, we will highlight key advances in the identification and expansion of antigen-specific Tregs and discuss their significance for cell therapy application.This perpetual progression has been the driving force behind the many successes to date and has put us now within touching distance of our ultimate success, immunological tolerance.

View Article: PubMed Central - PubMed

Affiliation: MRC Centre for Transplantation, Division of Transplantation Immunology and Mucosal Biology, Faculty of Life Sciences and Medicine, King's College London , London , UK.

ABSTRACT
Regulatory T cells (Tregs) play an important role in immunoregulation and have been shown in animal models to promote transplantation tolerance and curb autoimmunity following their adoptive transfer. The safety and potential therapeutic efficacy of these cells has already been reported in Phase I trials of bone-marrow transplantation and type I diabetes, the success of which has motivated the broadened application of these cells in solid-organ transplantation. Despite major advances in the clinical translation of these cells, there are still key questions to be addressed to ensure that Tregs attest their reputation as ideal candidates for tolerance induction. In this review, we will discuss the unique traits of Tregs that have attracted such fame in the arena of tolerance induction. We will outline the protocols used for their ex vivo expansion and discuss the future directions of Treg cell therapy. In this regard, we will review the concept of Treg heterogeneity, the desire to isolate and expand a functionally superior Treg population and report on the effect of differing culture conditions. The relevance of Treg migratory capacity will also be discussed together with methods of in vivo visualization of the infused cells. Moreover, we will highlight key advances in the identification and expansion of antigen-specific Tregs and discuss their significance for cell therapy application. We will also summarize the clinical parameters that are of importance, alongside cell manufacture, from the choice of immunosuppression regimens to the number of injections in order to direct the success of future efficacy trials of Treg cell therapy. Years of research in the field of tolerance have seen an accumulation of knowledge and expertise in the field of Treg biology. This perpetual progression has been the driving force behind the many successes to date and has put us now within touching distance of our ultimate success, immunological tolerance.

No MeSH data available.


Related in: MedlinePlus

Immunological targets for immunosuppressive drugs in T cells. Drugs can affect specific molecular pathways and control gene expression to block alloactivation of T cell after transplantation and induce tolerance. Abbreviations: TCR, T-cell receptor; mTOR, mammalian target of rapamycin; MMF, mycophenolate mofetil; PI3K, phosphatidylinositol 3-kinase; IL-2R, interleukin-2 receptor; NFkB, nuclear factor κ-light-chain-enhancer of activated B cells; MAPK, mitogen-activated protein kinase; NFAT, nuclear factor of activated T-cells.
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Figure 3: Immunological targets for immunosuppressive drugs in T cells. Drugs can affect specific molecular pathways and control gene expression to block alloactivation of T cell after transplantation and induce tolerance. Abbreviations: TCR, T-cell receptor; mTOR, mammalian target of rapamycin; MMF, mycophenolate mofetil; PI3K, phosphatidylinositol 3-kinase; IL-2R, interleukin-2 receptor; NFkB, nuclear factor κ-light-chain-enhancer of activated B cells; MAPK, mitogen-activated protein kinase; NFAT, nuclear factor of activated T-cells.

Mentions: This immunosuppressant mechanism of action involves the inhibition of the mammalian target of rapamycin (mTOR), which is downstream of phosphatidylinositol 3-kinase (PI3K), a signaling molecule activated by CD28 or IL-2 receptor engagement in T cells (75) (Figure 3). Characteristically, IL-2 receptor engagement activates both PI3K-mTOR and Janus kinase-STAT pathways. However, biochemical analysis of IL-2 signaling in Tregs has shown that the PI3K–mTOR pathway is underactive, whereas the Janus Kinase–STAT pathway remains intact, suggesting that Tregs preferentially signal through the latter in turn conferring their resistance to mTOR inhibition (76). In agreement, genetic ablation and cellular experiments that demonstrate mTOR deficiency or the addition of rapamycin favor the growth and preserved function of Tregs (77, 78). Paralleling these in vitro observations, it has been shown that rapamycin can potentiate the ability of Tregs to inhibit transplant arteriosclerosis in a humanized mouse system (79). Furthermore, in transplant patients, the use of rapamycin-based immunosuppression is also associated with an increased proportion of Tregs as compared to patients on calcineurin inhibitors (CNI) (80, 81). Thus, by favoring Treg survival and expansion and by preventing the outgrowth of contaminating effector T cells (76, 82), rapamycin ensures the selection of a pure Treg population.


Regulatory T Cells: Serious Contenders in the Promise for Immunological Tolerance in Transplantation.

Safinia N, Scotta C, Vaikunthanathan T, Lechler RI, Lombardi G - Front Immunol (2015)

Immunological targets for immunosuppressive drugs in T cells. Drugs can affect specific molecular pathways and control gene expression to block alloactivation of T cell after transplantation and induce tolerance. Abbreviations: TCR, T-cell receptor; mTOR, mammalian target of rapamycin; MMF, mycophenolate mofetil; PI3K, phosphatidylinositol 3-kinase; IL-2R, interleukin-2 receptor; NFkB, nuclear factor κ-light-chain-enhancer of activated B cells; MAPK, mitogen-activated protein kinase; NFAT, nuclear factor of activated T-cells.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4553385&req=5

Figure 3: Immunological targets for immunosuppressive drugs in T cells. Drugs can affect specific molecular pathways and control gene expression to block alloactivation of T cell after transplantation and induce tolerance. Abbreviations: TCR, T-cell receptor; mTOR, mammalian target of rapamycin; MMF, mycophenolate mofetil; PI3K, phosphatidylinositol 3-kinase; IL-2R, interleukin-2 receptor; NFkB, nuclear factor κ-light-chain-enhancer of activated B cells; MAPK, mitogen-activated protein kinase; NFAT, nuclear factor of activated T-cells.
Mentions: This immunosuppressant mechanism of action involves the inhibition of the mammalian target of rapamycin (mTOR), which is downstream of phosphatidylinositol 3-kinase (PI3K), a signaling molecule activated by CD28 or IL-2 receptor engagement in T cells (75) (Figure 3). Characteristically, IL-2 receptor engagement activates both PI3K-mTOR and Janus kinase-STAT pathways. However, biochemical analysis of IL-2 signaling in Tregs has shown that the PI3K–mTOR pathway is underactive, whereas the Janus Kinase–STAT pathway remains intact, suggesting that Tregs preferentially signal through the latter in turn conferring their resistance to mTOR inhibition (76). In agreement, genetic ablation and cellular experiments that demonstrate mTOR deficiency or the addition of rapamycin favor the growth and preserved function of Tregs (77, 78). Paralleling these in vitro observations, it has been shown that rapamycin can potentiate the ability of Tregs to inhibit transplant arteriosclerosis in a humanized mouse system (79). Furthermore, in transplant patients, the use of rapamycin-based immunosuppression is also associated with an increased proportion of Tregs as compared to patients on calcineurin inhibitors (CNI) (80, 81). Thus, by favoring Treg survival and expansion and by preventing the outgrowth of contaminating effector T cells (76, 82), rapamycin ensures the selection of a pure Treg population.

Bottom Line: The relevance of Treg migratory capacity will also be discussed together with methods of in vivo visualization of the infused cells.Moreover, we will highlight key advances in the identification and expansion of antigen-specific Tregs and discuss their significance for cell therapy application.This perpetual progression has been the driving force behind the many successes to date and has put us now within touching distance of our ultimate success, immunological tolerance.

View Article: PubMed Central - PubMed

Affiliation: MRC Centre for Transplantation, Division of Transplantation Immunology and Mucosal Biology, Faculty of Life Sciences and Medicine, King's College London , London , UK.

ABSTRACT
Regulatory T cells (Tregs) play an important role in immunoregulation and have been shown in animal models to promote transplantation tolerance and curb autoimmunity following their adoptive transfer. The safety and potential therapeutic efficacy of these cells has already been reported in Phase I trials of bone-marrow transplantation and type I diabetes, the success of which has motivated the broadened application of these cells in solid-organ transplantation. Despite major advances in the clinical translation of these cells, there are still key questions to be addressed to ensure that Tregs attest their reputation as ideal candidates for tolerance induction. In this review, we will discuss the unique traits of Tregs that have attracted such fame in the arena of tolerance induction. We will outline the protocols used for their ex vivo expansion and discuss the future directions of Treg cell therapy. In this regard, we will review the concept of Treg heterogeneity, the desire to isolate and expand a functionally superior Treg population and report on the effect of differing culture conditions. The relevance of Treg migratory capacity will also be discussed together with methods of in vivo visualization of the infused cells. Moreover, we will highlight key advances in the identification and expansion of antigen-specific Tregs and discuss their significance for cell therapy application. We will also summarize the clinical parameters that are of importance, alongside cell manufacture, from the choice of immunosuppression regimens to the number of injections in order to direct the success of future efficacy trials of Treg cell therapy. Years of research in the field of tolerance have seen an accumulation of knowledge and expertise in the field of Treg biology. This perpetual progression has been the driving force behind the many successes to date and has put us now within touching distance of our ultimate success, immunological tolerance.

No MeSH data available.


Related in: MedlinePlus