Low-dose Interleukin-2 in the Treatment of Autoimmune Disease

Oncology & Hematology Review, 2014;10(2):157–63

Abstract:

CD4+ regulatory T cells (Tregs) act to maintain peripheral immune tolerance. Decreased numbers or defective function of Tregs has been implicated in the pathogenesis of various autoimmune diseases. Interleukin-2 (IL-2) at high doses is approved by the US Food and Drug Administration (FDA) as an immune stimulant to induce anti-tumor cytotoxicity. However, at physiologic doses, IL-2 is necessary for the expansion and function of Tregs. Treatment with low-dose IL-2 can selectively enhance Treg function while avoiding the activation of effector T cells and ameliorate immune inflammation. Administration of low doses of IL-2 to patients suffering from chronic graft versus host disease (cGvHD) or chronic hepatitis C-mediated vasculitis resulted in significant clinical benefit, which was linked to improved Treg cell function. Preclinical studies suggest that low-dose IL-2 may offer benefit in other autoimmune diseases including systemic lupus erythematosus and type 1 diabetes. Ongoing preclinical and clinical studies indicate a wider potential role for low-dose IL-2 based Treg therapeutics in human autoimmune diseases.

Keywords: Autoimmune disease, interleukin-2, systemic lupus erythematosus, graft versus host disease, vasculitis, type-1 diabetes
Disclosure: John Koreth, MBBS, DPhil, has received research funding from Prometheus. Jerome Ritz, MD, has received research funding from Prometheus. Michelle Rosenzwajg, MD, PhD, is an inventor of a patent application claiming low-dose interleukin-2 (IL-2) in autoimmune and inflammatory diseases, owned by her academic institutions and licensed to ILTOO Pharma in which she holds shares. David Klatzmann, MD, PhD, is an inventor of a patent application claiming low-dose IL-2 in autoimmune and inflammatory diseases, owned by his academic institutions and licensed to ILTOO Pharma in which he holds shares. George C Tsokos, MD, Alberto Pugliese, MD, and Thomas R Malek, PhD, have no conflicts of interest to declare.
Acknowledgments: Editorial assistance was provided by Katrina Mountfort, PhD, at Touch Medical Media, London, UK and funded by Prometheus.
Received: October 22, 2014 Accepted November 06, 2014 Citation Oncology & Hematology Review, 2014;10(2):157–63
Correspondence: John Koreth, MBBS, DPhil, D2029 Dana Faber Cancer Institute, 450 Brookline Ave, Boston, MA 02215, US (E: john_koreth@dfci.harvard.edu). George C Tsokos, MD, 330 Brookline Avenue, CLS 937, Boston, MA 02115, US (E: gtsokos@bidmc.harvard.edu).
Support: The publication of this article was supported by Prometheus. The views and opinions expressed are those of the authors and do not necessarily reflect those of Prometheus.

Autoimmune diseases comprise more than 80 chronic conditions that collectively affect approximately 5 to 8 % of the US population and are a leading cause of death in young and middle-aged women.1 Moreover, the incidence and prevalence of autoimmune diseases are rising. The age of onset of autoimmune diseases varies widely but many start during childhood2 and, being chronic and debilitating in nature, require long-term therapy and invoke considerable medical costs, long-term impaired quality of life, and constitute a significant burden to families and society. Type 1 diabetes (T1D), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and inflammatory bowel disease (IBD) account for the majority of the patients with autoimmune diseases. Understanding the dysregulated immune response underlying autoimmune diseases will help the development of disease-specific therapeutics. In this short review we will present an overview of the pathophysiology of autoimmune diseases in the context of regulatory T cell (Treg) dysfunction with a focus on the emerging role for interleukin-2 (IL-2) based Treg therapeutics in restoring immune regulation and mitigating organ damage.

Pathophysiology of Autoimmune Disease— The Role of Tregs
Autoimmune diseases are characterized by a breakdown of mechanisms that allow the immune system to distinguish between self and nonself and maintain immunologic self-tolerance. Organ damage and the ensuing clinical manifestations may result from the action of autoantibodies, self-reactive effector T cell (Teff) responses, secreted cytokines, or other elements that participate in the autoimmune response.3 In recent years, there has been increasing interest in the role of Tregs, which are important in the maintenance of peripheral immune tolerance.4 Tregs can suppress immunemediated inflammation through a number of complementary mechanisms that may involve cell–cell contact and the release of regulatory cytokines that directly limit the responses of effector immune cells.

Several subtypes of Tregs exist, the most well studied being CD4+ cells that express high-level CD25 and the transcription factor forkhead box P3 (FOXP3), which is a critical determinant of Treg cell phenotype and function. Treg deficiency or dysfunction is associated with autoimmune disease. For example, in experimental animal studies, genetic or pharmacologic depletion of Tregs causes autoimmunity.5,6

Mutations of the FOXP3 gene in humans result in impaired Treg function and are associated with the ‘immunodysregulation polyendocrinopathy enteropathy X-linked’ (IPEX) syndrome, a rare disorder characterized by fulminant multi-organ autoimmunity.7 In clinical studies, decreased levels of circulating CD25+CD4+ T cells have been reported in patients with autoimmune disease, including vasculitis, rheumatic disease, juvenile idiopathic arthritis, and Kawasaki disease,8–12 and are associated with high disease activity or poor prognosis.8,10,12 Graft versus host disease (GvHD), which is a manifestation of allo-immunity following hematopoietic stem cell transplantation (HSCT), has also been associated with Treg cell deficiency.

These data have led to the hypothesis that augmentation of Tregs may be a useful therapeutic strategy in autoimmune disease. Treg augmentation has resulted in clinical improvements in numerous animal models of autoimmune diseases.13 Furthermore, the administration of in vitro expanded CD4+CD25highCD127-Tregs has been found to be safe and may help to preserve β-cell function in children with T1D.14,15 Targeting Treg cell enhancement at the cellular and molecular levels may therefore be an attractive therapeutic strategy. Cytokines that can modulate and boost Treg-mediated suppression of immune responses may play an important role in the control of autoimmunity. This article will focus on the ability of IL-2 to augment the numbers and function of CD4+ Tregs.

References:
  1. AAARD, Autoimmune statistics. Available at: http://www.aarda. org/autoimmune-information/autoimmune-statistics/ (accessed August 4, 2014).
  2. Amador-Patarroyo MJ, Rodriguez-Rodriguez A, Montoya-Ortiz G, How does age at onset influence the outcome of autoimmune diseases?, Autoimmune Dis, 2012;2012:251730.
  3. Bluestone JA, Mechanisms of tolerance, Immunol Rev, 2011;241:5–19.
  4. Belkaid Y, Tarbell K, Regulatory T cells in the control of host-microorganism interactions (*), Annu Rev Immunol, 2009;27:551–89.
  5. Wing K, Sakaguchi S, Regulatory T cells exert checks and balances on self tolerance and autoimmunity, Nat Immunol, 2010;11:7–13.
  6. Geng X, Zhang R, Yang G, et al., Interleukin-2 and autoimmune disease occurrence and therapy, Eur Rev Med Pharmacol Sci, 2012;16:1462–7.
  7. d’Hennezel E, Ben-Shoshan M, Ochs HD, et al., FOXP3 forkhead domain mutation and regulatory T cells in the IPEX syndrome, N Engl J Med, 2009;361:1710–3.
  8. de Kleer IM, Wedderburn LR, Taams LS, et al., CD4+CD25bright regulatory T cells actively regulate inflammation in the joints of patients with the remitting form of juvenile idiopathic arthritis, J Immunol, 2004;172:6435–43.
  9. Cao D, van Vollenhoven R, Klareskog L, et al., CD25brightCD4+ regulatory T cells are enriched in inflamed joints of patients with chronic rheumatic disease, Arthritis Res Ther, 2004;6:R335–46.
  10. Boyer O, Saadoun D, Abriol J, et al., CD4+CD25+ regulatory T-cell deficiency in patients with hepatitis C-mixed cryoglobulinemia vasculitis, Blood, 2004;103:3428–30.
  11. Kuhn A, Beissert S, Krammer PH, CD4(+)CD25 (+) regulatory T cells in human lupus erythematosus, Arch Dermatol Res, 2009;301:71–81.
  12. Furuno K, Yuge T, Kusuhara K, et al., CD25+CD4+ regulatory T cells in patients with Kawasaki disease, J Pediatr, 2004;145:385–90.
  13. Brusko TM, Putnam AL, Bluestone JA, Human regulatory T cells: role in autoimmune disease and therapeutic opportunities, Immunol Rev, 2008;223:371–90.
  14. Marek-Trzonkowska N, Mysliwiec M, Dobyszuk A, et al., Therapy of type 1 diabetes with CD4(+)CD25(high)CD127-regulatory T cells prolongs survival of pancreatic islets – results of one year follow-up, Clin Immunol, 2014;153:23–30.
  15. Marek-Trzonkowska N, Mysliwiec M, Dobyszuk A, et al., Administration of CD4+CD25highCD127- regulatory T cells preserves beta-cell function in type 1 diabetes in children, Diabetes Care, 2012;35:1817–20.
  16. Malek TR, The main function of IL-2 is to promote the development of T regulatory cells, J Leukoc Biol, 2003;74:961–5.
  17. Setoguchi R, Hori S, Takahashi T, et al., Homeostatic maintenance of natural Foxp3(+) CD25(+) CD4(+) regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization, J Exp Med, 2005;201:723–35.
  18. Malek TR, Bayer AL, Tolerance, not immunity, crucially depends on IL-2, Nat Rev Immunol, 2004;4:665–74.
  19. Yu A, Zhu L, Altman NH, et al., A low interleukin-2 receptor signaling threshold supports the development and homeostasis of T regulatory cells, Immunity, 2009;30:204–17.
  20. Shevach EM, Application of IL-2 therapy to target T regulatory cell function, Trends Immunol, 2012;33:626–32.
  21. Baecher-Allan C, Wolf E, Hafler DA, Functional analysis of highly defined, FACS-isolated populations of human regulatory CD4+ CD25+ T cells, Clin Immunol, 2005;115:10–8.
  22. Laurence A, Tato CM, Davidson TS, et al., Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation, Immunity, 2007;26:371–81.
  23. Ballesteros-Tato A, Leon B, Graf BA, et al., Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation, Immunity, 2012;36:847–56.
  24. Richter GH, Mollweide A, Hanewinkel K, et al., CD25 blockade protects T cells from activation-induced cell death (AICD) via maintenance of TOSO expression, Scand J Immunol, 2009;70:206–15.
  25. Boyman O, Sprent J, The role of interleukin-2 during homeostasis and activation of the immune system, Nat Rev Immunol, 2012;12:180–90.
  26. Kovacs B, Vassilopoulos D, Vogelgesang SA, et al., Defective CD3-mediated cell death in activated T cells from patients with systemic lupus erythematosus: role of decreased intracellular TNF-alpha, Clin Immunol Immunopathol, 1996;81:293–302.
  27. Lieberman LA, Tsokos GC, The IL-2 defect in systemic lupus erythematosus disease has an expansive effect on host immunity, J Biomed Biotechnol, 2010;2010:740619.
  28. Zier KS, Leo MM, Spielman RS, et al., Decreased synthesis of interleukin-2 (IL-2) in insulin-dependent diabetes mellitus, Diabetes, 1984;33:552–5.
  29. Roncarolo MG, Zoppo M, Bacchetta R, et al., Interleukin-2 production and interleukin-2 receptor expression in children with newly diagnosed diabetes, Clin Immunol Immunopathol, 1988;49:53–62.
  30. Giordano C, Panto F, Caruso C, et al., Interleukin 2 and soluble interleukin 2-receptor secretion defect in vitro in newly diagnosed type I diabetic patients, Diabetes, 1989;38:310–5.
  31. Kitas GD, Salmon M, Farr M, et al., Deficient interleukin 2 production in rheumatoid arthritis: association with active disease and systemic complications, Clin Exp Immunol, 1988;73:242–9.
  32. Sadlack B, Merz H, Schorle H, et al., Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene, Cell, 1993;75:253–61.
  33. Tsokos GC, Thai TH, Interleukin-2 in systemic autoimmunity hits the micro way, Arthritis Rheum, 2012;64:3494–7.
  34. Konya C, Paz Z, Tsokos GC, The role of T cells in systemic lupus erythematosus: an update, Curr Opin Rheumatol, 2014;26:493–501.
  35. Koga T, Ichinose K, Mizui M, et al., Calcium/calmodulindependent protein kinase IV suppresses IL-2 production and regulatory T cell activity in lupus, J Immunol, 2012;189:3490–6.
  36. Tsokos GC, Systemic lupus erythematosus, N Engl J Med, 2011;365:2110–21.
  37. Solomou EE, Juang YT, Gourley MF, et al., Molecular basis of deficient IL-2 production in T cells from patients with systemic lupus erythematosus, J Immunol, 2001;166:4216–22.
  38. Hedrich CM, Crispin JC, Rauen T, et al., cAMP response element modulator alpha controls IL2 and IL17A expression during CD4 lineage commitment and subset distribution in lupus, Proc Natl Acad Sci U S A, 2012;109:16606–11.
  39. Bluestone JA, The yin and yang of interleukin-2-mediated immunotherapy, N Engl J Med, 2011;365:2129–31.
  40. Moulton VR, Holcomb DR, Zajdel MC, et al., Estrogen upregulates cyclic AMP response element modulator alpha expression and downregulates interleukin-2 production by human T lymphocytes, Mol Med, 2012;18:370–8.
  41. Iliopoulos AG, Tsokos GC, Immunopathogenesis and spectrum of infections in systemic lupus erythematosus, Semin Arthritis Rheum, 1996;25:318–36.
  42. Hartemann A, Bensimon, G, Payan CA, et al., Low-dose interleukin 2 in patients with type 1 diabetes: a phase 1/2 randomised, double-blind, placebo-controlled trial, Lancet Diabetes Endocrinol, 2013;1:295–305.
  43. Matsuoka K, Koreth J, Kim HT, et al., Low-dose interleukin-2 therapy restores regulatory T cell homeostasis in patients with chronic graft-versus-host disease, Sci Transl Med, 2013;5:179ra43.
  44. Hao J, Campagnolo D, Liu R, et al., Interleukin-2/interleukin-2 antibody therapy induces target organ natural killer cells that inhibit central nervous system inflammation, Ann Neurol, 2011;69:721–34.
  45. Dutcher J, Atkins MB, Margolin K, et al., Kidney cancer: the Cytokine Working Group experience (1986–2001): part II. Management of IL-2 toxicity and studies with other cytokines, Med Oncol, 2001;18:209–19.
  46. Group I-ES, Committee SS, Abrams D, et al., Interleukin-2 therapy in patients with HIV infection, N Engl J Med, 2009;361:1548–59.
  47. de Vries IJ, Castelli C, Huygens C, et al., Frequency of circulating Tregs with demethylated FOXP3 intron 1 in melanoma patients receiving tumor vaccines and potentially Treg-depleting agents, Clin Cancer Res, 2011;17:841–8.
  48. Ahmadzadeh M, Rosenberg SA, IL-2 administration increases CD4+ CD25(hi) Foxp3+ regulatory T cells in cancer patients, Blood, 2006;107:2409–14.
  49. Boyman O, Kovar M, Rubinstein MP, et al., Selective stimulation of T cell subsets with antibody-cytokine immune complexes, Science, 2006;311:1924–7.
  50. d’Hennezel E, Kornete M, Piccirillo CA, IL-2 as a therapeutic target for the restoration of Foxp3+ regulatory T cell function in organ-specific autoimmunity: implications in pathophysiology and translation to human disease, J Transl Med, 2010;8:113.
  51. Aoyama A, Klarin D, Yamada Y, et al., Low-dose IL-2 for in vivo expansion of CD4+ and CD8+ regulatory T cells in nonhuman primates, Am J Transplant, 2012;12:2532–7.
  52. Mizui M, Koga T, Lieberman LA, et al., IL-2 Protects lupus-prone mice from multiple end-organ damage by limiting CD4-CD8- IL- 17-producing T cells, J Immunol, 2014;193:2168–77.
  53. Rouse M, Nagarkatti M, Nagarkatti PS, The role of IL-2 in the activation and expansion of regulatory T-cells and the development of experimental autoimmune encephalomyelitis, Immunobiology, 2013;218:674–82.
  54. Webster KE, Walters S, Kohler RE, et al., 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, 2009;206:751–60.
  55. Tang Q, Adams JY, Penaranda C, et al., Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction, Immunity, 2008;28:687–97.
  56. Grinberg-Bleyer Y, Baeyens A, You S, et al., IL-2 reverses established type 1 diabetes in NOD mice by a local effect on pancreatic regulatory T cells, J Exp Med, 2010;207:1871–8.
  57. Johnson MC, Garland AL, Nicolson SC, et al., Beta-cell-specific IL-2 therapy increases islet Foxp3+Treg and suppresses type 1 diabetes in NOD mice, Diabetes, 2013;62:3775–84.
  58. Goudy KS, Johnson MC, Garland A, et al., Inducible adenoassociated virus-mediated IL-2 gene therapy prevents autoimmune diabetes, J Immunol, 2011;186:3779–86.
  59. Diaz-de-Durana Y, Lau J, Knee D, et al., IL-2 Immunotherapy reveals potential for innate beta cell regeneration in the nonobese diabetic mouse model of autoimmune diabetes, PLoS One, 2013;8:e78483.
  60. Dirice E, Kahraman S, Jiang W, et al., Soluble factors secreted by T cells promote beta-cell proliferation, Diabetes, 2014;63:188–202.
  61. Soiffer RJ, Murray C, Cochran K, et al., Clinical and immunologic effects of prolonged infusion of low-dose recombinant interleukin-2 after autologous and T-cell-depleted allogeneic bone marrow transplantation, Blood, 1992;79:517–26.
  62. Soiffer RJ, Murray C, Gonin R, et al., Effect of low-dose interleukin-2 on disease relapse after T-cell-depleted allogeneic bone marrow transplantation, Blood, 1994;84:964–71.
  63. Zorn E, Nelson EA, Mohseni M, et al., IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo, Blood, 2006;108:1571–9.
  64. Shah MH, Freud AG, Benson DM, Jr, et al., A phase I study of ultra low dose interleukin-2 and stem cell factor in patients with HIV infection or HIV and cancer, Clin Cancer Res, 2006;12:3993–6.
  65. Saadoun D, Rosenzwajg M, Joly F, et al., Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis, N Engl J Med, 2011;365:2067–77.
  66. Koreth J, Matsuoka K, Kim HT, et al., Interleukin-2 and regulatory T cells in graft-versus-host disease, N Engl J Med, 2011;365:2055–66.
  67. Castela E, Le Duff F, Butori C, et al., Effects of low-dose recombinant interleukin 2 to promote T-regulatory cells in alopecia areata, JAMA Dermatol, 2014;150:748–51.
  68. Induction of regulatory T Cells by low-dose Il2 in autoimmune and Inflammatory Diseases (TRANSREG) Available at: http:// clinicaltrials.gov/show/NCT01988506 (accessed August 5, 2014).
  69. Waldron-Lynch F, Kareclas P, Irons K, et al., Rationale and study design of the Adaptive study of IL-2 dose on regulatory T cells in type 1 diabetes (DILT1D): a non-randomised, open label, adaptive dose finding trial, BMJ Open, 2014;4:e005559.
  70. Ultra-low dose Interleukin-2 to fight T1D trial (DIABL-2). Available at: http://www.diabil-2.eu/ (accessed October 6, 2014).
  71. Ito S, Bollard CM, Carlsten M, et al., Ultra-low dose interleukin-2 promotes immune-modulating function of regulatory T cells and natural killer cells in healthy volunteers, Mol Ther, 2014;22:1388–95.
  72. Klein Wolterink RG, Kleinjan A, van Nimwegen M, et al., Pulmonary innate lymphoid cells are major producers of IL-5 and IL-13 in murine models of allergic asthma, Eur J Immunol, 2012;42:1106–16.
  73. Humrich JY, von Spree C, Rose A, et al., Induction of remission by low-dose IL-2-therapy in one SLE patient with increased disease activity refractory to standard therapies: A case report, Ann Rhem Dis, 2014;73:A46.
  74. Klatzmann D, Immunoregulation without immunosuppression: the promise of low-dose IL2. Presented at the FOCiS meeting, June 25–28, 2014, Chicago, Illinois.
  75. Yu D, Low-dose interleukin-2 in active systemic lupus erythematosus, presented at the FOCiS meeting, June 25–28 2014, Chicago, Illinois.
  76. Lalezari JP, Beal JA, Ruane PJ, et al., Low-dose daily subcutaneous interleukin-2 in combination with highly active antiretroviral therapy in HIV+ patients: a randomized controlled trial, HIV Clin Trials, 2000;1:1–15.
  77. Lotze MT, Frana LW, Sharrow SO, et al., In vivo administration of purified human interleukin 2. I. Half-life and immunologic effects of the Jurkat cell line-derived interleukin 2, J Immunol, 1985;134:157–66.
  78. Piscitelli SC, Wells MJ, Metcalf JA, et al., Pharmacokinetics and pharmacodynamics of subcutaneous interleukin-2 in HIVinfected patients, Pharmacotherapy, 1996;16:754–9.
  79. Letourneau S, van Leeuwen EM, Krieg C, et al., IL-2/anti-IL-2 antibody complexes show strong biological activity by avoiding interaction with IL-2 receptor alpha subunit CD25, Proc Natl Acad Sci U S A, 2010;107:2171–6.
  80. Liu R, Zhou Q, La Cava A, et al., Expansion of regulatory T cells via IL-2/anti-IL-2 mAb complexes suppresses experimental myasthenia, Eur J Immunol, 2010;40:1577–89.
  81. Monti P, Scirpoli M, Maffi P, et al., Rapamycin monotherapy in patients with type 1 diabetes modifies CD4+CD25+FOXP3+ regulatory T-cells, Diabetes, 2008;57:2341–7.
  82. Kopf H, de la Rosa GM, Howard OM, et al., Rapamycin inhibits differentiation of Th17 cells and promotes generation of FoxP3+ T regulatory cells, Int Immunopharmacol, 2007;7:1819–24.
  83. Long SA, Buckner JH, Combination of rapamycin and IL-2 increases de novo induction of human CD4(+)CD25(+)FOXP3(+) T cells, J Autoimmun, 2008;30:293–302.
  84. Rabinovitch A, Suarez-Pinzon WL, Shapiro AM, et al., Combination therapy with sirolimus and interleukin-2 prevents spontaneous and recurrent autoimmune diabetes in NOD mice, Diabetes, 2002;51:638–45.
  85. Long SA, Rieck M, Sanda S, et al., Rapamycin/IL-2 combination therapy in patients with type 1 diabetes augments Tregs yet transiently impairs beta-cell function, Diabetes, 2012;61:2340–8.
  86. Baeyens A, Perol L, Fourcade G, et al., Limitations of IL-2 and rapamycin in immunotherapy of type 1 diabetes, Diabetes, 2013;62:3120–31.
  87. Barlow AD, Nicholson ML, Herbert TP, Evidence for rapamycin toxicity in pancreatic beta-cells and a review of the underlying molecular mechanisms, Diabetes, 2013;62:2674–82.
  88. Zorn E, Mohseni M, Kim H, et al., Combined CD4+ donor lymphocyte infusion and low-dose recombinant IL-2 expand FOXP3+ regulatory T cells following allogeneic hematopoietic stem cell transplantation, Biol Blood Marrow Transplant, 2009;15:382–8.
  89. Lapierre P, Beland K, Yang R, et al., Adoptive transfer of ex vivo expanded regulatory T cells in an autoimmune hepatitis murine model restores peripheral tolerance, Hepatology, 2013;57:217–27.
  90. Riley JL, June CH, Blazar BR, Human T regulatory cell therapy: take a billion or so and call me in the morning, Immunity, 2009;30:656–65.
  91. Churlaud G, Jimenez V, Ruberte J, et al., Sustained stimulation and expansion of Tregs by IL2 control autoimmunity without impairing immune responses to infection, vaccination and cancer, Clin Immunol, 2014;151:114–26.
  92. Kennedy-Nasser AA, Ku S, Castillo-Caro P, et al., Ultra low-dose IL-2 for GVHD prophylaxis after allogeneic hematopoietic stem cell transplantation mediates expansion of regulatory T cells without diminishing antiviral and antileukemic activity, Clin Cancer Res, 2014;20:2215–25.
Keywords: Autoimmune disease, interleukin-2, systemic lupus erythematosus, graft versus host disease, vasculitis, type-1 diabetes