Characterization of in vitro antimurine thymocyte globulin-induced regulatory T cells that inhibit graft-versus-host disease in vivo.
Antithymocyte/antilymphocyte globulins are polyclonal antihuman T-cell antibodies used clinically to treat acute transplant rejection. These reagents deplete T cells, but a rabbit antihuman thymocyte globulin has also been shown to induce regulatory T cells in vitro. To examine whether antithymocyte globulin-induced regulatory cells might be functional in vivo, we generated a corresponding rabbit antimurine thymocyte globulin (mATG) and tested its ability to induce regulatory cells in vitro and whether those cells can inhibit acute graft-versus-host disease (GVHD) in vivo upon adoptive transfer. In vitro, mATG induces a population of CD4(+)CD25(+) T cells that express several cell surface molecules representative of regulatory T cells. These cells do not express Foxp3 at either the protein or mRNA level, but do show suppressive function both in vitro and in vivo when adoptively transferred into a model of GVHD. These results demonstrate that in a murine system, antithymocyte globulin induces cells with suppressive activity that also function in vivo to protect against acute GVHD. Thus, in both murine and human systems, antithymocyte globulins not only deplete T cells, but also appear to generate regulatory cells. The in vitro generation of regulatory cells by anti-thymocyte globulins could provide ad-ditional therapeutic modalities for immune-mediated disease.
Ruzek
Melanie C
MC
Immunology and Clinical Laboratory Sciences, Biologics R&D, Framingham, MA, USA. melanie.ruzek@genzyme.com
Waire
James S
JS
Hopkins
Deborah
D
Lacorcia
Gina
G
Sullivan
Jennifer
J
Roberts
Bruce L
BL
Richards
Susan M
SM
Nahill
Sharon R
SR
Williams
John M
JM
Scaria
Abraham
A
Dzuris
John
J
Shankara
Srinivas
S
Garman
Richard D
RD
D000818:Animals; D000961:Antilymphocyte Serum / Q000276:immunology* / Q000494:pharmacology; D015415:Biomarkers; D049109:Cell Proliferation; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006086:Graft vs Host Disease / Q000276:immunology* / Q000517:prevention & control*; D016753:Interleukin-10 / Q000096:biosynthesis; D051379:Mice; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
D000961:Antilymphocyte Serum; D015415:Biomarkers; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D016212:Transforming Growth Factor beta; D016753:Interleukin-10