Favorable effects of alemtuzumab on allospecific regulatory T-cell generation

Josh Levitsky, Joseph R. Leventhal, Joshua Miller, Xuemei Huang, Li Chen, Dhivya Chandrasekaran, Anat R. Tambur, James M. Mathew*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

We studied the effects of alemtuzumab on T-regulatory cells (Tregs) during alloactivation, first by differences in depletion of various naive versus alloactivated cell subsets in peripheral blood of healthy volunteers, then by adding serial concentrations to human leukocyte antigen (HLA)-DR-matched and -mismatched responding and stimulating cells in mixed lymphocyte reaction (MLR). Lymphoproliferation inhibition and the development of proliferating carboxyfluorescein succinimidyl ester (CFSE)-diluted CD4 +CD25 highCD127 -FOXP3 + (phenotypic) Tregs by flow cytometry were measured. Also, the ability of alemtuzumab-treated versus nontreated MLR generated CD4 +CD127 - cells to allospecifically inhibit MLRs and recruit additional responding Tregs was tested. We found a more pronounced refractoriness of alloactivated versus naive CD4 +CD25 high cells to alemtuzumab induced lymphodepletion. Alemtuzumab dose dependently inhibited lymphoproliferation while amplifying percentages of MLR-generated Tregs. This was somewhat augmented by human complement addition. CD127 -CD4 + cells immunoselected after 7 days from alemtuzumab-treated MLRs allospecifically inhibited lymphoproliferation and recruited additional Tregs in fresh MLR-responding cells, similar to modulators derived from MLRs without drug addition (media). Addition of tacrolimus and sirolimus to alemtuzumab further inhibited MLR proliferation. However, Treg percentages were markedly higher with sirolimus. These results support the notion that alemtuzumab induces immunoregulation in naïve T cells undergoing alloactivation absent presensitization, especially used in conjunction with maintenance SRL.

Original languageEnglish (US)
Pages (from-to)141-149
Number of pages9
JournalHuman Immunology
Volume73
Issue number2
DOIs
StatePublished - Feb 2012

Keywords

  • Alemtuzumab
  • FOXP3
  • MTOR inhibition
  • Mixed lymphocyte reaction
  • Regulatory T cells

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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