Contrasting Effects of Cyclosporine and Rapamycin in De Novo Generation of Alloantigen‐Specific Regulatory T Cells

The outcome of T‐cell‐mediated responses, immunity or tolerance, critically depends on the balance of cytopathic versus regulatory T (Treg) cells. In the creation of stable tolerance to MHC incompatible allografts, reducing the unusually large mass of donor‐reactive cytopathic T effector (Teff) cells via apoptosis is often required. Cyclosporine (CsA) blocks activation‐induced cell death (AICD) of Teff cells, and is detrimental to tolerance induction by costimulation blockade, whereas Rapamycin (RPM) preserves AICD, and augments the potential of costimulation blockade to create tolerance. While differences between CsA and RPM in influencing apoptosis of activated graft‐destructive Teff cells are apparent, their effects on graft‐protective Treg cells remain enigmatic. Moreover, it is unclear whether tolerizing regimens foster conversion of naïve peripheral T cells into alloantigen‐specific Treg cells for graft protection. Here we show, using reporter mice for Treg marker Foxp3, that RPM promotes de novo conversion of alloantigen‐specific Treg cells, whereas CsA completely inhibits this process. Upon transfer, in vivo converted Treg cells potently suppress the rejection of donor but not third party skin grafts. Thus, the differential effects of RPM and CsA on Teff and Treg cells favor the use of RPM in shifting the balance of aggressive to protective type alloimmunity.

• Publication year

  2007

• Venue

  American Journal of Transplantation

• Publication date

  2007-04-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1111/j.1600-6143.2007.01842.xPMID 17511761PMCID PMC3831357
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Pillars Article: Control of Regulatory T Cell Development by the Transcription Factor Foxp3. Science 2003. 299: 1057-1061.

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  2006cited by this paper
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  2006cited by this paper
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  2006influential reference
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  2006cited by this paper
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  2006cited by this paper
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  2006cited by this paper
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  2006cited by this paper
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  2006cited by this paper
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  2005cited by this paper
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  2005cited by this paper
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  2005cited by this paper
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  2005cited by this paper
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  2005cited by this paper
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  2005cited by this paper
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  2005cited by this paper
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  2005cited by this paper
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  2003cited by this paper
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  1991influential reference

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