SEARCH:   Advanced

Blood, 15 June 2005, Vol. 105, No. 12, pp. 4743-4748. Prepublished online as a Blood First Edition Paper on March 3, 2005; DOI 10.1182/blood-2004-10-3932. This Article Full Text (PDF) All Versions of this Article: 2004-10-3932v1 105/12/4743    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Battaglia, M. Articles by Roncarolo, M.-G. Search for Related Content PubMed PubMed Citation Articles by Battaglia, M. Articles by Roncarolo, M.-G. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 13, 2004 Accepted February 14, 2005 Rapamycin selectively expands CD4+CD25+FOXP3+ regulatory T cells Manuela Battaglia, Angela Stabilini, and Maria-Grazia Roncarolo* San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milan, Italy San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milan, Italy; Vita Salute San Raffaele University, Milan, Italy * Corresponding author; email: m.roncarolo{at}hsr.it. Rapamycin is an immunosuppressive compound that is currently used to prevent acute graft rejection in humans. In addition, rapamycin has been shown to allow operational tolerance in murine models. However, a direct effect of rapamycin on T regulatory (Tr) cells, which play a key role in induction and maintenance of peripheral tolerance, has not been demonstrated so far. Here we provide new evidence that rapamycin selectively expands the murine naturally occurring CD4+CD25+FOXP3+ Tr cells in vitro. These expanded Tr cells suppress proliferation of syngeneic T cells in vitro and prevent allograft rejection in vivo. Interestingly, rapamycin does not block activation induced cell death and proliferation of CD4+ T cells in vitro. Based on this new mode of action, rapamycin can be used to expand CD4+CD25+FOXP3+ Tr cells for ex-vivo cellular therapy in T-cell-mediated diseases. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Ex vivo expansion of CD4+CD25+ T regulatory cells Elizabeth H. Field Blood 2005 105: 4542-4543. [Full Text] [PDF] This article has been cited by other articles: M. Pierau, S. Engelmann, D. Reinhold, T. Lapp, B. Schraven, and U. H. Bommhardt Protein Kinase B/Akt Signals Impair Th17 Differentiation and Support Natural Regulatory T Cell Function and Induced Regulatory T Cell Formation J. Immunol., November 15, 2009; 183(10): 6124 - 6134. [Abstract] [Full Text] [PDF] S. A. De Serres, M. H. Sayegh, and N. Najafian Immunosuppressive Drugs and Tregs: A Critical Evaluation! Clin. J. Am. Soc. Nephrol., October 1, 2009; 4(10): 1661 - 1669. [Abstract] [Full Text] [PDF] L. C. Chen, J. C. Delgado, P. E. Jensen, and X. Chen Direct Expansion of Human Allospecific FoxP3+CD4+ Regulatory T Cells with Allogeneic B Cells for Therapeutic Application J. Immunol., September 15, 2009; 183(6): 4094 - 4102. [Abstract] [Full Text] [PDF] A.-L. RIVAL-TRINGALI, S. EUVRARD, E. DECULLIER, A. CLAUDY, M. FAURE, and J. KANITAKIS Conversion from Calcineurin Inhibitors to Sirolimus Reduces Vascularization and Thickness of Post-transplant Cutaneous Squamous Cell Carcinomas Anticancer Res, June 1, 2009; 29(6): 1927 - 1932. [Abstract] [Full Text] [PDF] X. Q. Lun, J.-H. Jang, N. Tang, H. Deng, R. Head, J. C. Bell, D. F. Stojdl, C. L. Nutt, D. L. Senger, P. A. Forsyth, et al. Efficacy of Systemically Administered Oncolytic Vaccinia Virotherapy for Malignant Gliomas Is Enhanced by Combination Therapy with Rapamycin or Cyclophosphamide Clin. Cancer Res., April 15, 2009; 15(8): 2777 - 2788. [Abstract] [Full Text] [PDF] K. E. Webster, S. Walters, R. E. Kohler, T. Mrkvan, O. Boyman, C. D. Surh, S. T. Grey, and J. Sprent In vivo expansion of T reg cells with IL-2-mAb complexes: induction of resistance to EAE and long-term acceptance of islet allografts without immunosuppression J. Exp. Med., April 13, 2009; 206(4): 751 - 760. [Abstract] [Full Text] [PDF] K. Nagahama, Z. Fehervari, T. Oida, T. Yamaguchi, O. Ogawa, and S. Sakaguchi Differential control of allo-antigen-specific regulatory T cells and effector T cells by anti-CD4 and other agents in establishing transplantation tolerance Int. Immunol., April 1, 2009; 21(4): 379 - 391. [Abstract] [Full Text] [PDF] A. Valle, T. Jofra, A. Stabilini, M. Atkinson, M.-G. Roncarolo, and M. Battaglia Rapamycin Prevents and Breaks the Anti-CD3-Induced Tolerance in NOD Mice Diabetes, April 1, 2009; 58(4): 875 - 881. [Abstract] [Full Text] [PDF] W. Zang, M. Lin, S. Kalache, N. Zhang, B. Kruger, A. M. Waaga-Gasser, M. Grimm, W. Hancock, P. Heeger, B. Schroppel, et al. Inhibition of the Alloimmune Response through the Generation of Regulatory T Cells by a MHC Class II-Derived Peptide J. Immunol., December 1, 2008; 181(11): 7499 - 7506. [Abstract] [Full Text] [PDF] J. Mariotti, J. Foley, K. Ryan, N. Buxhoeveden, V. Kapoor, S. Amarnath, and D. H. Fowler Graft rejection as a Th1-type process amenable to regulation by donor Th2-type cells through an interleukin-4/STAT6 pathway Blood, December 1, 2008; 112(12): 4765 - 4775. [Abstract] [Full Text] [PDF] W. Reichardt, C. Durr, D. von Elverfeldt, E. Juttner, U. V. Gerlach, M. Yamada, B. Smith, R. S. Negrin, and R. Zeiser Impact of Mammalian Target of Rapamycin Inhibition on Lymphoid Homing and Tolerogenic Function of Nanoparticle-Labeled Dendritic Cells following Allogeneic Hematopoietic Cell Transplantation J. Immunol., October 1, 2008; 181(7): 4770 - 4779. [Abstract] [Full Text] [PDF] K. L. Hippen, P. Harker-Murray, S. B. Porter, S. C. Merkel, A. Londer, D. K. Taylor, M. Bina, A. Panoskaltsis-Mortari, P. Rubinstein, N. Van Rooijen, et al. Umbilical cord blood regulatory T-cell expansion and functional effects of tumor necrosis factor receptor family members OX40 and 4-1BB expressed on artificial antigen-presenting cells Blood, October 1, 2008; 112(7): 2847 - 2857. [Abstract] [Full Text] [PDF] R. E. Mills, K. R. Taylor, K. Podshivalova, D. B. McKay, and J. M. Jameson Defects in Skin {gamma}{delta} T Cell Function Contribute to Delayed Wound Repair in Rapamycin-Treated Mice J. Immunol., September 15, 2008; 181(6): 3974 - 3983. [Abstract] [Full Text] [PDF] R. Nishimura, J. Baker, A. Beilhack, R. Zeiser, J. A. Olson, E. I. Sega, M. Karimi, and R. S. Negrin In vivo trafficking and survival of cytokine-induced killer cells resulting in minimal GVHD with retention of antitumor activity Blood, September 15, 2008; 112(6): 2563 - 2574. [Abstract] [Full Text] [PDF] P. Monti, M. Scirpoli, P. Maffi, L. Piemonti, A. Secchi, E. Bonifacio, M.-G. Roncarolo, and M. Battaglia Rapamycin Monotherapy in Patients With Type 1 Diabetes Modifies CD4+CD25+FOXP3+ Regulatory T-Cells Diabetes, September 1, 2008; 57(9): 2341 - 2347. [Abstract] [Full Text] [PDF] T. N. Golovina, T. Mikheeva, M. M. Suhoski, N. A. Aqui, V. C. Tai, X. Shan, R. Liu, R. R. Balcarcel, N. Fisher, B. L. Levine, et al. CD28 Costimulation Is Essential for Human T Regulatory Expansion and Function J. Immunol., August 15, 2008; 181(4): 2855 - 2868. [Abstract] [Full Text] [PDF] K. Hochegger, G. L. Jansky, A. Soleiman, A. M. Wolf, A. Tagwerker, C. Seger, A. Griesmacher, G. Mayer, and A. R. Rosenkranz Differential Effects of Rapamycin in Anti-GBM Glomerulonephritis J. Am. Soc. Nephrol., August 1, 2008; 19(8): 1520 - 1529. [Abstract] [Full Text] [PDF] H. R. Turnquist, T. L. Sumpter, A. Tsung, A. F. Zahorchak, A. Nakao, G. J. Nau, F. Y. Liew, D. A. Geller, and A. W. Thomson IL-1{beta}-Driven ST2L Expression Promotes Maturation Resistance in Rapamycin-Conditioned Dendritic Cells J. Immunol., July 1, 2008; 181(1): 62 - 72. [Abstract] [Full Text] [PDF] Z.-R. Yuan and Y. Shi Chloramphenicol Induces Abnormal Differentiation and Inhibits Apoptosis in Activated T Cells Cancer Res., June 15, 2008; 68(12): 4875 - 4881. [Abstract] [Full Text] [PDF] S. Sauer, L. Bruno, A. Hertweck, D. Finlay, M. Leleu, M. Spivakov, Z. A. Knight, B. S. Cobb, D. Cantrell, E. O'Connor, et al. T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR PNAS, June 3, 2008; 105(22): 7797 - 7802. [Abstract] [Full Text] [PDF] J. Kang, S. J. Huddleston, J. M. Fraser, and A. Khoruts De novo induction of antigen-specific CD4+CD25+Foxp3+ regulatory T cells in vivo following systemic antigen administration accompanied by blockade of mTOR J. Leukoc. Biol., May 1, 2008; 83(5): 1230 - 1239. [Abstract] [Full Text] [PDF] S. Basu, T. Golovina, T. Mikheeva, C. H. June, and J. L. Riley Cutting Edge: Foxp3-Mediated Induction of Pim 2 Allows Human T Regulatory Cells to Preferentially Expand in Rapamycin J. Immunol., May 1, 2008; 180(9): 5794 - 5798. [Abstract] [Full Text] [PDF] S. Haxhinasto, D. Mathis, and C. Benoist The AKT-mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells J. Exp. Med., March 17, 2008; 205(3): 565 - 574. [Abstract] [Full Text] [PDF] J. Mariotti, J. Foley, U. Jung, T. Borenstein, N. Kantardzic, S. Han, J. T. Hanson, E. Wong, N. Buxhoeveden, J. B. Trepel, et al. Ex Vivo Rapamycin Generates Apoptosis-Resistant Donor Th2 Cells That Persist In Vivo and Prevent Hemopoietic Stem Cell Graft Rejection J. Immunol., January 1, 2008; 180(1): 89 - 105. [Abstract] [Full Text] [PDF] R. Zeiser, D. B. Leveson-Gower, E. A. Zambricki, N. Kambham, A. Beilhack, J. Loh, J.-Z. Hou, and R. S. Negrin Differential impact of mammalian target of rapamycin inhibition on CD4+CD25+Foxp3+ regulatory T cells compared with conventional CD4+ T cells Blood, January 1, 2008; 111(1): 453 - 462. [Abstract] [Full Text] [PDF] K. G. Elpek, E. S. Yolcu, D. D. H. Franke, C. Lacelle, R.-H. Schabowsky, and H. Shirwan Ex Vivo Expansion of CD4+CD25+FoxP3+ T Regulatory Cells Based on Synergy between IL-2 and 4-1BB Signaling J. Immunol., December 1, 2007; 179(11): 7295 - 7304. [Abstract] [Full Text] [PDF] A. Giorgini and A. Noble Blockade of chronic graft-versus-host disease by alloantigen-induced CD4+CD25+Foxp3+ regulatory T cells in nonlymphopenic hosts J. Leukoc. Biol., November 1, 2007; 82(5): 1053 - 1061. [Abstract] [Full Text] [PDF] Y.-H. Lee, Y.-R. Lee, S.-A Im, S.-I. Park, K.-H. Kim, T. Gerelchuluun, S. Song, K. Kim, and C.-K. Lee Calcineurin Inhibitors Block MHC-Restricted Antigen Presentation In Vivo J. Immunol., November 1, 2007; 179(9): 5711 - 5716. [Abstract] [Full Text] [PDF] A. Ramos-Barron, C. Pinera-Haces, C. Gomez-Alamillo, I. Santiuste-Torcida, J.C. Ruiz, L. Buelta-Carrillo, R. Merino, A.L.M. de Francisco, and M. Arias Prevention of murine lupus disease in (NZBxNZW)F1 mice by sirolimus treatment Lupus, October 1, 2007; 16(10): 775 - 781. [Abstract] [PDF] O. Bestard, J. M. Cruzado, M. Mestre, A. Caldes, J. Bas, M. Carrera, J. Torras, I. Rama, F. Moreso, D. Seron, et al. Achieving Donor-Specific Hyporesponsiveness Is Associated with FOXP3+ Regulatory T Cell Recruitment in Human Renal Allograft Infiltrates J. Immunol., October 1, 2007; 179(7): 4901 - 4909. [Abstract] [Full Text] [PDF] F. Mingozzi, N. C. Hasbrouck, E. Basner-Tschakarjan, S. A. Edmonson, D. J. Hui, D. E. Sabatino, S. Zhou, J. F. Wright, H. Jiang, G. F. Pierce, et al. Modulation of tolerance to the transgene product in a nonhuman primate model of AAV-mediated gene transfer to liver Blood, October 1, 2007; 110(7): 2334 - 2341. [Abstract] [Full Text] [PDF] V. Sanchez-Guajardo, C. Tanchot, J. T. O'Malley, M. H. Kaplan, S. Garcia, and A. A. Freitas Agonist-Driven Development of CD4+CD25+Foxp3+ Regulatory T Cells Requires a Second Signal Mediated by Stat6 J. Immunol., June 15, 2007; 178(12): 7550 - 7556. [Abstract] [Full Text] [PDF] H. R. Turnquist, G. Raimondi, A. F. Zahorchak, R. T. Fischer, Z. Wang, and A. W. Thomson Rapamycin-Conditioned Dendritic Cells Are Poor Stimulators of Allogeneic CD4+ T Cells, but Enrich for Antigen-Specific Foxp3+ T Regulatory Cells and Promote Organ Transplant Tolerance J. Immunol., June 1, 2007; 178(11): 7018 - 7031. [Abstract] [Full Text] [PDF] C. Cutler, S. Li, V. T. Ho, J. Koreth, E. Alyea, R. J. Soiffer, and J. H. Antin Extended follow-up of methotrexate-free immunosuppression using sirolimus and tacrolimus in related and unrelated donor peripheral blood stem cell transplantation Blood, April 1, 2007; 109(7): 3108 - 3114. [Abstract] [Full Text] [PDF] M. Noris, F. Casiraghi, M. Todeschini, P. Cravedi, D. Cugini, G. Monteferrante, S. Aiello, L. Cassis, E. Gotti, F. Gaspari, et al. Regulatory T Cells and T Cell Depletion: Role of Immunosuppressive Drugs J. Am. Soc. Nephrol., March 1, 2007; 18(3): 1007 - 1018. [Abstract] [Full Text] [PDF] D. Golshayan, S. Jiang, J. Tsang, M. I. Garin, C. Mottet, and R. I. Lechler In vitro-expanded donor alloantigen-specific CD4+CD25+ regulatory T cells promote experimental transplantation tolerance Blood, January 15, 2007; 109(2): 827 - 835. [Abstract] [Full Text] [PDF] L. Strauss, T. L. Whiteside, A. Knights, C. Bergmann, A. Knuth, and A. Zippelius Selective Survival of Naturally Occurring Human CD4+CD25+Foxp3+ Regulatory T Cells Cultured with Rapamycin J. Immunol., January 1, 2007; 178(1): 320 - 329. [Abstract] [Full Text] [PDF] E. Kreijveld, H. J. P. M. Koenen, L. B. Hilbrands, H. J. P. van Hooff, and I. Joosten The immunosuppressive drug FK778 induces regulatory activity in stimulated human CD4+CD25- T cells Blood, January 1, 2007; 109(1): 244 - 252. [Abstract] [Full Text] [PDF] M. Battaglia, A. Stabilini, B. Migliavacca, J. Horejs-Hoeck, T. Kaupper, and M.-G. Roncarolo Rapamycin Promotes Expansion of Functional CD4+CD25+FOXP3+ Regulatory T Cells of Both Healthy Subjects and Type 1 Diabetic Patients J. Immunol., December 15, 2006; 177(12): 8338 - 8347. [Abstract] [Full Text] [PDF] M. Lopez, M. R. Clarkson, M. Albin, M. H. Sayegh, and N. Najafian A Novel Mechanism of Action for Anti-Thymocyte Globulin: Induction of CD4+CD25+Foxp3+ Regulatory T Cells J. Am. Soc. Nephrol., October 1, 2006; 17(10): 2844 - 2853. [Abstract] [Full Text] [PDF] N. Najafian, M. J. Albin, and K. A. Newell How Can We Measure Immunologic Tolerance in Humans? J. Am. Soc. Nephrol., October 1, 2006; 17(10): 2652 - 2663. [Abstract] [Full Text] [PDF] D. M. Rothstein Immunosuppression and Regulation: Cast in New Light? J. Am. Soc. Nephrol., October 1, 2006; 17(10): 2644 - 2646. [Full Text] [PDF] D. Valmori, V. Tosello, N. E. Souleimanian, E. Godefroy, L. Scotto, Y. Wang, and M. Ayyoub Rapamycin-Mediated Enrichment of T Cells with Regulatory Activity in Stimulated CD4+ T Cell Cultures Is Not Due to the Selective Expansion of Naturally Occurring Regulatory T Cells but to the Induction of Regulatory Functions in Conventional CD4+ T Cells J. Immunol., July 15, 2006; 177(2): 944 - 949. [Abstract] [Full Text] [PDF] R. Zeiser, V. H. Nguyen, A. Beilhack, M. Buess, S. Schulz, J. Baker, C. H. Contag, and R. S. Negrin Inhibition of CD4+CD25+ regulatory T-cell function by calcineurin-dependent interleukin-2 production Blood, July 1, 2006; 108(1): 390 - 399. [Abstract] [Full Text] [PDF] M. Battaglia, A. Stabilini, E. Draghici, B. Migliavacca, S. Gregori, E. Bonifacio, and M.-G. Roncarolo Induction of Tolerance in Type 1 Diabetes via Both CD4+CD25+ T Regulatory Cells and T Regulatory Type 1 Cells Diabetes, June 1, 2006; 55(6): 1571 - 1580. [Abstract] [Full Text] [PDF] B. Blanco, J. A. Perez-Simon, L. I. Sanchez-Abarca, X. Carvajal-Vergara, J. Mateos, B. Vidriales, N. Lopez-Holgado, P. Maiso, M. Alberca, E. Villaron, et al. Bortezomib induces selective depletion of alloreactive T lymphocytes and decreases the production of Th1 cytokines Blood, May 1, 2006; 107(9): 3575 - 3583. [Abstract] [Full Text] [PDF] P.-Y. Mantel, N. Ouaked, B. Ruckert, C. Karagiannidis, R. Welz, K. Blaser, and C. B. Schmidt-Weber Molecular Mechanisms Underlying FOXP3 Induction in Human T Cells J. Immunol., March 15, 2006; 176(6): 3593 - 3602. [Abstract] [Full Text] [PDF] J. J. A. Coenen, H. J. P. M. Koenen, E. van Rijssen, L. B. Hilbrands, and I. Joosten Rapamycin, and not cyclosporin A, preserves the highly suppressive CD27+ subset of human CD4+CD25+ regulatory T cells Blood, February 1, 2006; 107(3): 1018 - 1023. [Abstract] [Full Text] [PDF] M. Battaglia, A. Stabilini, E. Draghici, S. Gregori, C. Mocchetti, E. Bonifacio, and M.-G. Roncarolo Rapamycin and Interleukin-10 Treatment Induces T Regulatory Type 1 Cells That Mediate Antigen-Specific Transplantation Tolerance Diabetes, January 1, 2006; 55(1): 40 - 49. [Abstract] [Full Text] [PDF] T. Muthukumar, D. Dadhania, R. Ding, C. Snopkowski, R. Naqvi, J. B. Lee, C. Hartono, B. Li, V. K. Sharma, S. V. Seshan, et al. Messenger RNA for FOXP3 in the urine of renal-allograft recipients. N. Engl. J. Med., December 1, 2005; 353(22): 2342 - 2351. [Abstract] [Full Text] [PDF]

	Copyright © 2005 by American Society of Hematology         Online ISSN: 1528-0020