540
Views
2
CrossRef citations to date
0
Altmetric
Review Articles

Low-dose IL-2 therapy in autoimmune diseases: An update review

, , , , & ORCID Icon
Pages 113-137 | Received 22 Mar 2023, Accepted 16 Oct 2023, Published online: 26 Oct 2023

Reference

  • IL2 interleukin 2 [Homo sapiens (human)] - Gene - NCBI. n.d. https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=DetailsSearch&Term=3558
  • Arenas-Ramirez N, Woytschak J, Boyman O. Interleukin-2: biology, design and application. Trends Immunol. 2015;36(12):763–777. doi:10.1016/j.it.2015.10.003.
  • Smith KA. Interleukin-2: inception, impact, and implications. Science. 1988;240(4856):1169–1176. doi:10.1126/science.3131876.
  • Liao W, Lin J-X, Leonard WJ. Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. Immunity. 2013;38(1):13–25. doi:10.1016/j.immuni.2013.01.004.
  • Buchbinder EI, Dutcher JP, Daniels GA, et al. Therapy with high-dose Interleukin-2 (HD IL-2) in metastatic melanoma and renal cell carcinoma following PD1 or PDL1 inhibition. J Immunother Cancer. 2019;7(1):49. doi:10.1186/s40425-019-0522-3.
  • Jiang T, Zhou C, Ren S. Role of IL-2 in cancer immunotherapy. Oncoimmunology. 2016;5(6):e1163462. doi:10.1080/2162402X.2016.1163462.
  • Choudhry H, Helmi N, Abdulaal WH, et al. Prospects of IL-2 in cancer immunotherapy, biomed. Biomed Res Int. 2018;2018:9056173. doi:10.1155/2018/9056173.
  • Bulgarelli J, Piccinini C, Petracci E, et al. Radiotherapy and high-dose interleukin-2: clinical and immunological results of a proof of principle study in metastatic melanoma and renal cell carcinoma. Front Immunol. 2021;12:778459. doi:10.3389/fimmu.2021.778459.
  • S R, S L, D J. Managing toxicities of high-dose interleukin-2, Oncol. Willist. Park N.Y. 2002;16:11–20. https://pubmed.ncbi.nlm.nih.gov/12469935/
  • Horak I, Löhler J, Ma A, et al. Interleukin-2 deficient mice: a new model to study autoimmunity and self-tolerance. Immunol Rev. 1995;148(1):35–44. doi:10.1111/j.1600-065x.1995.tb00092.x.
  • Furtado GC, Curotto De Lafaille MA, Kutchukhidze N, et al. Interleukin 2 signaling is required for CD4(+) regulatory T cell function. J Exp Med. 2002;196(6):851–857. doi:10.1084/jem.20020190.
  • Barron L, Dooms H, Hoyer KK, et al. Cutting edge: mechanisms of IL-2-dependent maintenance of functional regulatory T cells. J Immunol. 2010;185(11):6426–6430. doi:10.4049/jimmunol.0903940.
  • Graßhoff H, Comdühr S, Monne LR, et al. Low-Dose IL-2 Therapy in Autoimmune and Rheumatic Diseases. Front Immunol. 2021;12:648408. doi:10.3389/fimmu.2021.648408.
  • He J, Zhang R, Shao M, et al. Efficacy and safety of low-dose IL-2 in the treatment of systemic lupus erythematosus: a randomised, double-blind, placebo-controlled trial. Ann Rheum Dis. 2020;79(1):141–149. doi:10.1136/annrheumdis-2019-215396.
  • 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(4):295–305. doi:10.1016/S2213-8587(13)70113-X.
  • Humrich JY, Morbach H, Undeutsch R, et al. Homeostatic imbalance of regulatory and effector T cells due to IL-2 deprivation amplifies murine lupus. Proc Natl Acad Sci U S A. 2010;107(1):204–209. doi:10.1073/pnas.0903158107.
  • Lee H, Son YS, Lee M-O, et al. Low-dose interleukin-2 alleviates dextran sodium sulfate-induced colitis in mice by recovering intestinal integrity and inhibiting AKT-dependent pathways. Theranostics. 2020;10(11):5048–5063. doi:10.7150/thno.41534.
  • Dutcher JP, Schwartzentruber DJ, Kaufman HL, et al. High dose interleukin-2 (Aldesleukin) - expert consensus on best management practices-2014. j. immunotherapy Cancer. 2014;2(1):26. doi:10.1186/s40425-014-0026-0.
  • Atkins MB, Kunkel L, Sznol M, et al. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J. Sci. Am. 2000;6(Suppl 1):S11–S14.
  • Ye C, Brand D, Zheng SG. Targeting IL-2: an unexpected effect in treating immunological diseases. Sig Transduct Target Ther. 2018;3(1):2. doi:10.1038/s41392-017-0002-5.
  • Zhang H, Chua KS, Guimond M, et al. Lymphopenia and interleukin-2 therapy alter homeostasis of CD4 + CD25+ regulatory T cells. Nat Med. 2005;11(11):1238–1243. doi:10.1038/nm1312.
  • Yuan Y, Kolios AGA, Liu Y, et al. Therapeutic potential of interleukin-2 in autoimmune diseases, Trends. Trends Mol Med. 2022;28(7):596–612. doi:10.1016/j.molmed.2022.04.010.
  • Cheng G, Yu A, Malek TR. T-cell tolerance and the multi-functional role of IL-2R signaling in T-regulatory cells. Immunol Rev. 2011;241(1):63–76. doi:10.1111/j.1600-065X.2011.01004.x.
  • Li Y, Li X, Geng X, et al. The IL-2A receptor pathway and its role in lymphocyte differentiation and function. Cytokine Growth Factor Rev. 2022;67:66–79. doi:10.1016/j.cytogfr.2022.06.004.
  • O’Shea JJ, Gadina M, Giuseppe S, et al. 14 - Cytokines and Cytokine Receptors. In: Rich RR, Fleisher TA, Schroeder HW, Weyand CM, Corry DB, Puck JM, editors. New Delhi: Elsevier; 2023. pp. 186–214. doi:10.1016/B978-0-7020-8165-1.00014-9.
  • Chen X, Oppenheim JJ. Resolving the identity myth: key markers of functional CD4 + FoxP3+ regulatory T cells. Int Immunopharmacol. 2011;11(10):1489–1496. doi:10.1016/j.intimp.2011.05.018.
  • Chen X, Oppenheim JJ. The phenotypic and functional consequences of tumour necrosis factor receptor type 2 expression on CD4(+) FoxP3(+) regulatory T cells. Immunology. 2011;133(4):426–433. doi:10.1111/j.1365-2567.2011.03460.x.
  • Jung MK, Lee JS, Kwak JE, et al. Tumor necrosis factor and regulatory T cells. Yonsei Med J. 2019;60(2):126–131. doi:10.3349/ymj.2019.60.2.126.
  • Delgoffe GM, Pollizzi KN, Waickman AT, et al. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat Immunol. 2011;12(4):295–303. doi:10.1038/ni.2005.
  • Wang R, Kozhaya L, Mercer F, et al. Expression of GARP selectively identifies activated human FOXP3+ regulatory T cells. Proc Natl Acad Sci U S A. 2009;106(32):13439–13444. doi:10.1073/pnas.0901965106.
  • Ghelani A, Bates D, Conner K, et al. Defining the threshold IL-2 signal required for induction of selective Treg cell responses using engineered IL-2 muteins. Front Immunol. 2020;11:1106. doi:10.3389/fimmu.2020.01106.
  • Colamatteo A, Carbone F, Bruzzaniti S, et al. Molecular mechanisms controlling Foxp3 expression in health and autoimmunity: from epigenetic to post-translational regulation. Front Immunol. 2019;10:3136. doi:10.3389/fimmu.2019.03136.
  • Lupov IP, Voiles L, Han L, et al. Acquired STAT4 deficiency as a consequence of cancer chemotherapy. Blood. 2011;118(23):6097–6106. doi:10.1182/blood-2011-03-341867.
  • Fan H, Yang J, Hao J, et al. Comparative study of regulatory T cells expanded ex vivo from cord blood and adult peripheral blood. Immunology. 2012;136(2):218–230. doi:10.1111/j.1365-2567.2012.03573.x.
  • Burugu S, Dancsok AR, Nielsen TO. Emerging targets in cancer immunotherapy. Semin Cancer Biol. 2018;52(Pt 2):39–52. doi:10.1016/j.semcancer.2017.10.001.
  • Bluestone JA, Trotta E, Xu D. The therapeutic potential of regulatory T cells for the treatment of autoimmune disease, Expert. Expert Opin Ther Targets. 2015;19(8):1091–1103. doi:10.1517/14728222.2015.1037282.
  • Plitas G, Rudensky AY. Regulatory T Cells: Differentiation and Function, Cancer. Cancer Immunol Res. 2016;4(9):721–725. doi:10.1158/2326-6066.CIR-16-0193.
  • Takeshita T, Asao H, Ohtani K, et al. Cloning of the gamma chain of the human IL-2 receptor. Science. 1992;257(5068):379–382. doi:10.1126/science.1631559.
  • Leonard WJ. The molecular basis of X-linked severe combined immunodeficiency: defective cytokine receptor signaling, Annu. Annu Rev Med. 1996;47:229–239. doi:10.1146/annurev.med.47.1.229.
  • N B, Lord J, G P. Cytoplasmic domains of the interleukin-2 receptor beta and gamma chains mediate the signal for T-cell proliferation. Nature. 1994;369(6478):333–336. doi:10.1038/369333a0.
  • Ross SH, Cantrell DA. Signaling and Function of Interleukin-2 in T Lymphocytes. Annu Rev Immunol. 2018;36(1):411–433. doi:10.1146/annurev-immunol-042617-053352.
  • Mitra S, Leonard WJ. Biology of IL-2 and its therapeutic modulation: Mechanisms and strategies. J Leukoc Biol. 2018;103(4):643–655. doi:10.1002/JLB.2RI0717-278R.
  • Su EW, Moore CJ, Suriano S, et al. IL-2Rα mediates temporal regulation of IL-2 signaling and enhances immunotherapy. Sci Transl Med. 2015;7(311):311ra170. doi:10.1126/scitranslmed.aac8155.
  • Peerlings D, Mimpen M, Damoiseaux J. The IL-2 - IL-2 receptor pathway: Key to understanding multiple sclerosis. J Transl Autoimmun. 2021;4:100123. doi:10.1016/j.jtauto.2021.100123.
  • Saadoun D, Rosenzwajg M, Joly F, et al. Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis, N. N Engl J Med. 2011;365(22):2067–2077. doi:10.1056/NEJMoa1105143.
  • 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(22):2055–2066. doi:10.1056/NEJMoa1108188.
  • Rosenberg SA, Yang JC, White DE, et al. Durability of complete responses in patients with metastatic cancer treated with high-dose interleukin-2: identification of the antigens mediating response. Ann Surg. 1998;228(3):307–319. doi:10.1097/00000658-199809000-00004.
  • Wu Y, Tian Z, Wei H. Developmental and Functional Control of Natural Killer Cells by Cytokines. Front Immunol. 2017;8:930. doi:10.3389/fimmu.2017.00930.
  • Kalia V, Sarkar S. Regulation of effector and memory CD8 T Cell differentiation by IL-2-A balancing act. Front Immunol. 2018;9:2987. doi:10.3389/fimmu.2018.02987.
  • Lin J-X, Li P, Liu D, et al. Critical Role of STAT5 transcription factor tetramerization for cytokine responses and normal immune function. Immunity. 2012;36(4):586–599. doi:10.1016/j.immuni.2012.02.017.
  • Kimura MY, Pobezinsky LA, Guinter TI, et al. IL-7 signaling must be intermittent, not continuous, during CD8+ T cell homeostasis to promote cell survival instead of cell death. Nat Immunol. 2013;14(2):143–151. doi:10.1038/ni.2494.
  • McGeachy MJ, Bak-Jensen KS, Chen Y, et al. TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol. 2007;8(12):1390–1397. doi:10.1038/ni1539.
  • Fontenot JD, Rasmussen JP, Williams LM, et al. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity. 2005;22(3):329–341. doi:10.1016/j.immuni.2005.01.016.
  • Yang J, Chu Y, Yang X, et al. Th17 and natural Treg cell population dynamics in systemic lupus erythematosus. Arthritis Rheum. 2009;60(5):1472–1483. doi:10.1002/art.24499.
  • Humrich JY, Riemekasten G. Low-dose interleukin-2 therapy for the treatment of systemic lupus erythematosus. Curr Opin Rheumatol. 2019;31(2):208–212. doi:10.1097/BOR.0000000000000575.
  • Wellbrock C, Karasarides M, Marais R. The RAF proteins take centre stage. Nat Rev Mol Cell Biol. 2004;5(11):875–885. doi:10.1038/nrm1498.
  • Schmitt EG, Williams CB. Generation and function of induced regulatory T cells. Front Immunol. 2013;4:152. doi:10.3389/fimmu.2013.00152.
  • Curotto De Lafaille MA, Lafaille JJ. Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor? Immunity. 2009;30(5):626–635. doi:10.1016/j.immuni.2009.05.002.
  • Toomer KH, Lui JB, Altman NH, et al. Essential and non-overlapping IL-2Rα-dependent processes for thymic development and peripheral homeostasis of regulatory T cells. Nat Commun. 2019;10(1):1037. doi:10.1038/s41467-019-08960-1.
  • 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(9):2532–2537. doi:10.1111/j.1600-6143.2012.04133.x.
  • Mahmud SA, Manlove LS, Farrar MA. Interleukin-2 and STAT5 in regulatory T cell development and function. JAKSTAT. 2013;2(1):e23154. doi:10.4161/jkst.23154.
  • Harding FA, McArthur JG, Gross JA, et al. CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones. Nature. 1992;356(6370):607–609. doi:10.1038/356607a0.
  • Fan MY, Low JS, Tanimine N, et al. Differential Roles of IL-2 Signaling in Developing versus Mature Tregs. Cell Rep. 2018;25(5):1204–1213.e4. doi:10.1016/j.celrep.2018.10.002.
  • Attias M, Al-Aubodah T, Piccirillo CA. Mechanisms of human FoxP3+ Treg cell development and function in health and disease. Clin Exp Immunol. 2019;197(1):36–51. doi:10.1111/cei.13290.
  • Zheng SG, Wang J, Wang P, et al. IL-2 is essential for TGF-beta to convert naive CD4 + CD25- cells to CD25 + Foxp3+ regulatory T cells and for expansion of these cells. J Immunol. 2007;178(4):2018–2027. doi:10.4049/jimmunol.178.4.2018.
  • Chinen T, Kannan AK, Levine AG, et al. An essential role for the IL-2 receptor in Treg cell function. Nat Immunol. 2016;17(11):1322–1333. doi:10.1038/ni.3540.
  • Liu Z, Gerner MY, Van Panhuys N, et al. Immune homeostasis enforced by co-localized effector and regulatory T cells. Nature. 2015;528(7581):225–230. doi:10.1038/nature16169.
  • Zhang M, Tang Q. Manipulating IL-2 and IL-2R in autoimmune diseases and transplantation. Immunotherapy. 2015;7(12):1231–1234. doi:10.2217/imt.15.94.
  • Tahvildari M, Dana R. Low-Dose IL-2 Therapy in Transplantation, Autoimmunity, and Inflammatory Diseases. J Immunol. 2019;203(11):2749–2755. doi:10.4049/jimmunol.1900733.
  • Long SA, Buckner JH. CD4 + FOXP3+ T regulatory cells in human autoimmunity: more than a numbers game. J Immunol. 2011;187(5):2061–2066. doi:10.4049/jimmunol.1003224.
  • Verreycken J, Baeten P, Broux B. Regulatory T cell therapy for multiple sclerosis: Breaching (blood-brain) barriers. Hum Vaccin Immunother. 2022;18(7):2153534. doi:10.1080/21645515.2022.2153534.
  • Danikowski KM, Jayaraman S, Prabhakar BS. Regulatory T cells in multiple sclerosis and myasthenia gravis. J Neuroinflammation. 2017;14(1):117. doi:10.1186/s12974-017-0892-8.
  • Mosmann TR, Cherwinski H, Bond MW, et al. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986;136(7):2348–2357. doi:10.4049/jimmunol.136.7.2348.
  • Martinez-Sanchez ME, Huerta L, Alvarez-Buylla ER, et al. Role of Cytokine Combinations on CD4+ T Cell Differentiation, Partial Polarization, and Plasticity: Continuous Network Modeling Approach. Front Physiol. 2018;9:877. doi:10.3389/fphys.2018.00877.
  • Luo J, Ming B, Zhang C, et al. IL-2 Inhibition of Th17 Generation Rather Than Induction of Treg Cells Is Impaired in Primary Sjögren’s Syndrome Patients. Front Immunol. 2018;9:1755. doi:10.3389/fimmu.2018.01755.
  • Ballesteros-Tato A, León B, Graf BA, et al. Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation. Immunity. 2012;36(5):847–856. doi:10.1016/j.immuni.2012.02.012.
  • Saravia J, Chapman NM, Chi H. Helper T cell differentiation. Cell Mol Immunol. 2019;16(7):634–643. doi:10.1038/s41423-019-0220-6.
  • Lee SK, Rigby RJ, Zotos D, et al. B cell priming for extrafollicular antibody responses requires Bcl-6 expression by T cells. J Exp Med. 2011;208(7):1377–1388. doi:10.1084/jem.20102065.
  • Huang J, Xu X, Yang J. miRNAs Alter T Helper 17 Cell Fate in the Pathogenesis of Autoimmune Diseases. Front Immunol. 2021;12:593473. doi:10.3389/fimmu.2021.593473.
  • Singh RP, Hasan S, Sharma S, et al. Th17 cells in inflammation and autoimmunity. Autoimmun Rev. 2014;13(12):1174–1181. doi:10.1016/j.autrev.2014.08.019.
  • Tokura Y. Th17 cells and skin diseases], Nihon Rinsho Men’eki Gakkai Kaishi = Jpn. Nihon Rinsho Meneki Gakkai Kaishi. 2012;35(5):388–392. [ doi:10.2177/jsci.35.388.
  • Tokura Y, Mori T, Hino R. Psoriasis and other Th17-mediated skin diseases. J Uoeh. 2010;32(4):317–328. doi:10.7888/juoeh.32.317.
  • He J, Zhang X, Wei Y, et al. Low-dose interleukin-2 treatment selectively modulates CD4(+) T cell subsets in patients with systemic lupus erythematosus. Nat Med. 2016;22(9):991–993. doi:10.1038/nm.4148.
  • Lee J, Baek S, Lee J, et al. Digoxin ameliorates autoimmune arthritis via suppression of Th17 differentiation. Int Immunopharmacol. 2015;26(1):103–111. doi:10.1016/j.intimp.2015.03.017.
  • Čolić M, Bekić M, Tomić S, et al. Immunomodulatory Properties of Pomegranate Peel Extract in a Model of Human Peripheral Blood Mononuclear Cell Culture. Pharmaceutics. 2022;14(6):1140. doi:10.3390/pharmaceutics14061140.
  • Konigsberg PJ, Godtel R, Kissel T, et al. The development of IL-2 conjugated liposomes for therapeutic purposes. Biochim Biophys Acta. 1998;1370(2):243–251. doi:10.1016/s0005-2736(97)00269-1.
  • Spangler JB, Tomala J, Luca VC, et al. Antibodies to Interleukin-2 Elicit Selective T Cell Subset Potentiation through Distinct Conformational Mechanisms. Immunity. 2015;42(5):815–825. doi:10.1016/j.immuni.2015.04.015.
  • Boyman O, Sprent J. The role of interleukin-2 during homeostasis and activation of the immune system. Nat Rev Immunol. 2012;12(3):180–190. doi:10.1038/nri3156.
  • Lee S-Y, Cho M-L, Oh H-J, et al. Interleukin-2/anti-interleukin-2 monoclonal antibody immune complex suppresses collagen-induced arthritis in mice by fortifying interleukin-2/STAT5 signalling pathways. Immunology. 2012;137(4):305–316. doi:10.1111/imm.12008.
  • Wilson MS, Pesce JT, Ramalingam TR, et al. Suppression of murine allergic airway disease by IL-2:anti-IL-2 monoclonal antibody-induced regulatory T cells. J Immunol. 2008;181(10):6942–6954. doi:10.4049/jimmunol.181.10.6942.
  • Yan J-J, Lee J-G, Jang JY, et al. IL-2/anti-IL-2 complexes ameliorate lupus nephritis by expansion of CD4 + CD25 + Foxp3+ regulatory T cells. Kidney Int. 2017;91(3):603–615. doi:10.1016/j.kint.2016.09.022.
  • Khoryati L, Pham MN, Sherve M, et al. An IL-2 mutein engineered to promote expansion of regulatory T cells arrests ongoing autoimmunity in mice. Sci Immunol. 2020;5(50):eaba5264. doi:10.1126/sciimmunol.aba5264.
  • Peterson LB, Bell CJM, Howlett SK, et al. A long-lived IL-2 mutein that selectively activates and expands regulatory T cells as a therapy for autoimmune disease. J Autoimmun. 2018;95:1–14. doi:10.1016/j.jaut.2018.10.017.
  • Arneth B. Systemic Lupus Erythematosus and DNA Degradation and Elimination Defects. Front Immunol. 2019;10:1697. doi:10.3389/fimmu.2019.01697.
  • Crispín JC, Morel L. Editorial: Mechanisms by Which SLE-Associated Genetic Variants Contribute to SLE Pathogenesis. Front Immunol. 2019;10:2808. doi:10.3389/fimmu.2019.02808.
  • Dai H, He F, Tsokos GC, et al. IL-23 Limits the Production of IL-2 and Promotes Autoimmunity in Lupus. J Immunol. 2017;199(3):903–910. doi:10.4049/jimmunol.1700418.
  • Kyttaris VC, Zhang Z, Kuchroo VK, et al. Cutting edge: IL-23 receptor deficiency prevents the development of lupus nephritis in C57BL/6-lpr/lpr mice. J Immunol. 2010;184(9):4605–4609. doi:10.4049/jimmunol.0903595.
  • Tackey E, Lipsky PE, Illei GG. Rationale for interleukin-6 blockade in systemic lupus erythematosus. Lupus. 2004;13(5):339–343. doi:10.1191/0961203304lu1023oa.
  • Mak A. T Cells, Interleukin-2 and Systemic Lupus Erythematosus-From Pathophysiology to Therapy. Cells. 2022;11(6):980. doi:10.3390/cells11060980.
  • Álvarez-Rodríguez L, Martínez-Taboada V, Calvo-Alén J, et al. Altered Th17/Treg Ratio in Peripheral Blood of Systemic Lupus Erythematosus but Not Primary Antiphospholipid Syndrome. Front Immunol. 2019;10:391. doi:10.3389/fimmu.2019.00391.
  • Humrich JY, Spee-Mayer CV, Siegert E, et al. Low-dose interleukin-2 therapy in refractory systemic lupus erythematosus: an investigator-initiated, single-centre phase 1 and 2a clinical trial. Lancet Rheumatol. 2019;1(1):e44–e54. doi:10.1016/S2665-9913(19)30018-9.
  • von Spee-Mayer C, Siegert E, Abdirama D, et al. Low-dose interleukin-2 selectively corrects regulatory T cell defects in patients with systemic lupus erythematosus. Ann Rheum Dis. 2016;75(7):1407–1415. doi:10.1136/annrheumdis-2015-207776.
  • Wang Z, Zhao M, Yin J, et al. E4BP4-mediated inhibition of T follicular helper cell differentiation is compromised in autoimmune diseases. J Clin Invest. 2020;130(7):3717–3733. doi:10.1172/JCI129018.
  • Iranparast S, Seif F, Tayebi S, et al. Essential Transcription Factors and Functional Roles of Follicular Helper T Cells in Human Autoimmune Diseases. Iran. j. Immunol.. 2022;19:121–138. doi:10.22034/iji.2022.92653.2164.
  • Miao M, Xiao X, Tian J, et al. Therapeutic potential of targeting Tfr/Tfh cell balance by low-dose-IL-2 in active SLE: a post hoc analysis from a double-blind RCT study. Arthritis Res Ther. 2021;23(1):167. doi:10.1186/s13075-021-02535-6.
  • Dixit N, Fanton C, Langowski JL, et al. NKTR-358: A novel regulatory T-cell stimulator that selectively stimulates expansion and suppressive function of regulatory T cells for the treatment of autoimmune and inflammatory diseases. J Transl Autoimmun. 2021;4:100103. doi:10.1016/j.jtauto.2021.100103.
  • Fanton C, Furie R, Chindalore V, et al. Selective expansion of regulatory T cells by NKTR-358 in healthy volunteers and patients with systemic lupus erythematosus. J Transl Autoimmun. 2022;5:100152. doi:10.1016/j.jtauto.2022.100152.
  • Tomita T. Apoptosis of pancreatic β-cells in Type 1 diabetes. Bosn J Basic Med Sci. 2017;17(3):183–193. doi:10.17305/bjbms.2017.1961.
  • Romagnani S. T-cell subsets (Th1 versus Th2). Ann Allergy Asthma Immunol. 2000;85(1):9–18; quiz 18, 21. doi:10.1016/S1081-1206(10)62426-X.
  • Arif S, Domingo-Vila C, Pollock E, et al. Monitoring islet specific immune responses in type 1 diabetes clinical immunotherapy trials. Front Immunol. 2023;14:1183909. doi:10.3389/fimmu.2023.1183909.
  • DePaolo RW, Abadie V, Tang F, et al. Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens. Nature. 2011;471(7337):220–224. doi:10.1038/nature09849.
  • Rosenzwajg M, Churlaud G, Hartemann A, et al. Interleukin 2 in the pathogenesis and therapy of type 1 diabetes. Curr Diab Rep. 2014;14(12):553. doi:10.1007/s11892-014-0553-6.
  • Chen Z, Lin F, Gao Y, et al. FOXP3 and RORγt: transcriptional regulation of Treg and Th17. Int Immunopharmacol. 2011;11(5):536–542. doi:10.1016/j.intimp.2010.11.008.
  • Noack M, Miossec P. Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. Autoimmun Rev. 2014;13(6):668–677. doi:10.1016/j.autrev.2013.12.004.
  • Corthay A. How do regulatory T cells work? Scand J Immunol. 2009;70(4):326–336. doi:10.1111/j.1365-3083.2009.02308.x.
  • Li J, Kim SG, Blenis J. Rapamycin: one drug, many effects. Cell Metab. 2014;19(3):373–379. doi:10.1016/j.cmet.2014.01.001.
  • Hu M, Hawthorne WJ, Nicholson L, et al. Low-Dose Interleukin-2 Combined With Rapamycin Led to an Expansion of CD4 + CD25 + FOXP3+ Regulatory T Cells and Prolonged Human Islet Allograft Survival in Humanized Mice. Diabetes. 2020;69(8):1735–1748. doi:10.2337/db19-0525.
  • Long SA, Rieck M, Sanda S, et al. Rapamycin/IL-2 combination therapy in patients with type 1 diabetes augments Tregs yet transiently impairs β-cell function. Diabetes. 2012;61(9):2340–2348. doi:10.2337/db12-0049.
  • Rosenzwajg M, Churlaud G, Mallone R, et al. Low-dose interleukin-2 fosters a dose-dependent regulatory T cell tuned milieu in T1D patients. J Autoimmun. 2015;58:48–58. doi:10.1016/j.jaut.2015.01.001.
  • Rosenzwajg M, Salet R, Lorenzon R, et al. Low-dose IL-2 in children with recently diagnosed type 1 diabetes: a Phase I/II randomised, double-blind, placebo-controlled, dose-finding study. Diabetologia. 2020;63(9):1808–1821. doi:10.1007/s00125-020-05200-w.
  • Dong S, Hiam-Galvez KJ, Mowery CT, et al. The effect of low-dose IL-2 and Treg adoptive cell therapy in patients with type 1 diabetes. JCI Insight. 2021;6(18):e147474. doi:10.1172/jci.insight.147474.
  • VanDyke D, Iglesias M, Tomala J, et al. Engineered human cytokine/antibody fusion proteins expand regulatory T cells and confer autoimmune disease protection. Cell Rep. 2022;41(3):111478. doi:10.1016/j.celrep.2022.111478.
  • Martinez-Cibrian N, Zeiser R, Perez-Simon JA. Graft-versus-host disease prophylaxis: Pathophysiology-based review on current approaches and future directions. Blood Rev. 2021;48:100792. doi:10.1016/j.blre.2020.100792.
  • Forcade E, Paz K, Flynn R, et al. An activated Th17-prone T cell subset involved in chronic graft-versus-host disease sensitive to pharmacological inhibition. JCI Insight. 2017;2(12):e92111. doi:10.1172/jci.insight.92111.
  • 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(179):179ra43. doi:10.1126/scitranslmed.3005265.
  • Bolivar-Wagers S, Loschi ML, Jin S, et al. Murine CAR19 Tregs suppress acute graft-versus-host disease and maintain graft-versus-tumor responses. JCI Insight. 2022;7(17):e160674. doi:10.1172/jci.insight.160674.
  • Jiang H, Fu D, Bidgoli A, et al. T Cell Subsets in Graft Versus Host Disease and Graft Versus Tumor. Front Immunol. 2021;12:761448. doi:10.3389/fimmu.2021.761448.
  • Wang W, Hong T, Wang X, et al. Newly Found Peacekeeper: Potential of CD8+ Tregs for Graft-Versus-Host Disease. Front Immunol. 2021;12:764786. doi:10.3389/fimmu.2021.764786.
  • Sullivan KM, Witherspoon RP, Storb R, et al. Prednisone and azathioprine compared with prednisone and placebo for treatment of chronic graft-v-host disease: prognostic influence of prolonged thrombocytopenia after allogeneic marrow transplantation. Blood. 1988;72(2):546–554. doi:10.1182/blood.V72.2.546.bloodjournal722546.
  • Flowers MED, Martin PJ. How we treat chronic graft-versus-host disease. Blood. 2015;125(4):606–615. doi:10.1182/blood-2014-08-551994.
  • Di Ianni M, Falzetti F, Carotti A, et al. Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. Blood. 2011;117(14):3921–3928. doi:10.1182/blood-2010-10-311894.
  • Koreth J, Kim HT, Jones KT, et al. Efficacy, durability, and response predictors of low-dose interleukin-2 therapy for chronic graft-versus-host disease. Blood. 2016;128(1):130–137. doi:10.1182/blood-2016-02-702852.
  • Pilon CB, Petillon S, Naserian S, et al. Administration of Low Doses of IL-2 Combined to Rapamycin Promotes Allogeneic Skin Graft Survival in Mice: IL-2 and Rapamycin Delay Skin Graft Rejection. Am J Transplant. 2014;14(12):2874–2882. doi:10.1111/ajt.12944.
  • Song Q, Wang X, Wu X, et al. Tolerogenic anti-IL-2 mAb prevents graft-versus-host disease while preserving strong graft-versus-leukemia activity. Blood. 2021;137(16):2243–2255. doi:10.1182/blood.2020006345.
  • Wolf D. GVHD prophylaxis: use an ortho IL-2/IL-2Rβ Treg system!. Blood. 2023;141(11):1246–1247. doi:10.1182/blood.2023019711.
  • Ramos TL, Bolivar-Wagers S, Jin S, et al. Prevention of acute GVHD using an orthogonal IL-2/IL-2Rβ system to selectively expand regulatory T cells in vivo. Blood. 2023;141(11):1337–1352. doi:10.1182/blood.2022018440.
  • Levine JE. More evidence for low-dose IL-2 for chronic GVHD in children. Blood Adv. 2023;7(16):4658–4659. doi:10.1182/bloodadvances.2023010756.
  • Guo Q, Wang Y, Xu D, et al. Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies. Bone Res. 2018;6(1):15. doi:10.1038/s41413-018-0016-9.
  • Rao DA, Gurish MF, Marshall JL, et al. Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis. Nature. 2017;542(7639):110–114. doi:10.1038/nature20810.
  • Wu R, Li N, Zhao X, et al. Low-dose Interleukin-2: Biology and therapeutic prospects in rheumatoid arthritis. Autoimmun Rev. 2020;19(10):102645. doi:10.1016/j.autrev.2020.102645.
  • Rosenzwajg M, Lorenzon R, Cacoub P, et al. Immunological and clinical effects of low-dose interleukin-2 across 11 autoimmune diseases in a single, open clinical trial. Ann Rheum Dis. 2019;78(2):209–217. doi:10.1136/annrheumdis-2018-214229.
  • Zhang S-X, Wang J, Wang C-H, et al. Low-dose IL-2 therapy limits the reduction in absolute numbers of circulating regulatory T cells in rheumatoid arthritis. Ther Adv Musculoskelet Dis. 2021;13:1759720X211011370. doi:10.1177/1759720X211011370.
  • Zhang R, Miao J, Zhang K, et al. Th1-Like Treg Cells Are Increased But Deficient in Function in Rheumatoid Arthritis. Front Immunol. 2022;13:863753. doi:10.3389/fimmu.2022.863753.
  • Furuyama K, Kondo Y, Shimizu M, et al. RORγt + Foxp3+ regulatory T cells in the regulation of autoimmune arthritis. Clin Exp Immunol. 2022;207(2):176–187. doi:10.1093/cei/uxab007.
  • Malemud CJ. Defective T-Cell apoptosis and t-regulatory cell dysfunction in rheumatoid arthritis. Cells. 2018;7(12):223. doi:10.3390/cells7120223.
  • Kotschenreuther K, Yan S, Kofler DM. Migration and homeostasis of regulatory T cells in rheumatoid arthritis. Front Immunol. 2022;13:947636. doi:10.3389/fimmu.2022.947636.
  • Yokoyama Y, Iwasaki T, Kitano S, et al. IL-2-Anti-IL-2 Monoclonal Antibody Immune Complexes Inhibit Collagen-Induced Arthritis by Augmenting Regulatory T Cell Functions. J Immunol. 2018;201(7):1899–1906. doi:10.4049/jimmunol.1701502.
  • Singh JA, Saag KG, Bridges SL, et al. 2015 American college of rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 2016;68(1):1–26. doi:10.1002/art.39480.
  • Sostres C, Gargallo CJ, Arroyo MT, et al. Adverse effects of non-steroidal anti-inflammatory drugs (NSAIDs, aspirin and coxibs) on upper gastrointestinal tract. Best Pract Res Clin Gastroenterol. 2010;24(2):121–132. doi:10.1016/j.bpg.2009.11.005.
  • Vonkeman HE, Van De Laar MAFJ. Nonsteroidal anti-inflammatory drugs: adverse effects and their prevention. Semin Arthritis Rheum. 2010;39(4):294–312. doi:10.1016/j.semarthrit.2008.08.001.
  • Saag KG, Koehnke R, Caldwell JR, et al. Low dose long-term corticosteroid therapy in rheumatoid arthritis: an analysis of serious adverse events. Am J Med. 1994;96(2):115–123. doi:10.1016/0002-9343(94)90131-7.
  • Yip RML, Yim CW. Role of interleukin 6 inhibitors in the management of rheumatoid arthritis. J Clin Rheumatol. 2021;27(8):e516–e524. doi:10.1097/RHU.0000000000001293.
  • Nam JL, Winthrop KL, Van Vollenhoven RF, et al. Current evidence for the management of rheumatoid arthritis with biological disease-modifying antirheumatic drugs: a systematic literature review informing the EULAR recommendations for the management of RA, Ann. Ann Rheum Dis. 2010;69(6):976–986. doi:10.1136/ard.2009.126573.
  • Teitsma XM, Marijnissen AKA, Bijlsma JWJ, et al. Tocilizumab as monotherapy or combination therapy for treating active rheumatoid arthritis: a meta-analysis of efficacy and safety reported in randomized controlled trials, Arthritis. Arthritis Res Ther. 2016;18(1):211. doi:10.1186/s13075-016-1108-9.
  • Sanmartí R, Ruiz-Esquide V, Bastida C, et al. Tocilizumab in the treatment of adult rheumatoid arthritis. Immunotherapy. 2018;10(6):447–464. doi:10.2217/imt-2017-0173.
  • Czaja AJ. Autoimmune hepatitis: surviving crises of doubt and elimination. Clin Liver Dis (Hoboken). 2020;15(Suppl 1):S72–S81. doi:10.1002/cld.917.
  • Robles DT, Eisenbarth GS. Immunology primer. Endocrinol Metab Clin North Am. 2002;31(2):261–282. doi:10.1016/s0889-8529(01)00016-0.
  • Luckheeram RV, Zhou R, Verma AD, et al. CD4+T cells: differentiation and functions, Clin. Clin Dev Immunol. 2012;2012:925135. doi:10.1155/2012/925135.
  • Liberal R, Grant CR, Holder BS, et al. In autoimmune hepatitis type 1 or the autoimmune hepatitis-sclerosing cholangitis variant defective regulatory T-cell responsiveness to IL-2 results in low IL-10 production and impaired suppression. Hepatology. 2015;62(3):863–875. doi:10.1002/hep.27884.
  • Buitrago-Molina LE, Pietrek J, Noyan F, et al. Treg-specific IL-2 therapy can reestablish intrahepatic immune regulation in autoimmune hepatitis. J Autoimmun. 2021;117:102591. doi:10.1016/j.jaut.2020.102591.
  • Oo YH, Ackrill S, Cole R, et al. Liver homing of clinical grade Tregs after therapeutic infusion in patients with autoimmune hepatitis. JHEP Rep. 2019;1(4):286–296. doi:10.1016/j.jhepr.2019.08.001.
  • Lim TY, Martinez-Llordella M, Kodela E, et al. Low-dose interleukin-2 for refractory autoimmune hepatitis. Hepatology. 2018;68(4):1649–1652. doi:10.1002/hep.30059.
  • Kolios AGA, Tsokos GC, Klatzmann D. Interleukin-2 and regulatory T cells in rheumatic diseases. Nat Rev Rheumatol. 2021;17(12):749–766. doi:10.1038/s41584-021-00707-x.
  • Rajabi F, Drake LA, Senna MM, et al. Alopecia areata: a review of disease pathogenesis. Br J Dermatol. 2018;179(5):1033–1048. doi:10.1111/bjd.16808.
  • Xing L, Dai Z, Jabbari A, et al. Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nat Med. 2014;20(9):1043–1049. doi:10.1038/nm.3645.
  • Craiglow BG, King BA. Killing two birds with one stone: oral tofacitinib reverses alopecia universalis in a patient with plaque psoriasis. J Invest Dermatol. 2014;134(12):2988–2990. doi:10.1038/jid.2014.260.
  • Liu LY, Craiglow BG, Dai F, et al. Tofacitinib for the treatment of severe alopecia areata and variants: A study of 90 patients. J Am Acad Dermatol. 2017;76(1):22–28. doi:10.1016/j.jaad.2016.09.007.
  • Shin BS, Furuhashi T, Nakamura M, et al. Impaired inhibitory function of circulating CD4 + CD25+ regulatory T cells in alopecia areata. J Dermatol Sci. 2013;70(2):141–143. doi:10.1016/j.jdermsci.2013.01.006.
  • 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(7):748–751. doi:10.1001/jamadermatol.2014.504.
  • Duff FL, Bouaziz J-D, Fontas E, et al. Low-Dose IL-2 for treating moderate to severe alopecia areata: A 52-week multicenter prospective placebo-controlled study assessing its impact on T regulatory cell and NK cell populations. J Invest Dermatol. 2021;141(4):933–936.e6. doi:10.1016/j.jid.2020.08.015.
  • Vollenberg R, Jouni R, Norris PAA, et al. Glycoprotein V is a relevant immune target in patients with immune thrombocytopenia. Haematologica. 2019;104(6):1237–1243. doi:10.3324/haematol.2018.211086.
  • Maher GM. Immune thrombocytopenia. S. D. Med.: J. S. D. State Med. Assoc. 2014;67:415–417.
  • Cines DB, Cuker A, Semple JW. Pathogenesis of immune thrombocytopenia. Presse Med. 2014;43(4 Pt 2):e49-59–e59. doi:10.1016/j.lpm.2014.01.010.
  • LeVine DN, Brooks MB. Immune thrombocytopenia (ITP): Pathophysiology update and diagnostic dilemmas. Vet Clin Pathol. 2019;48(Suppl S1):17–28. doi:10.1111/vcp.12774.
  • Li J, Sullivan JA, Ni H. Pathophysiology of immune thrombocytopenia, Curr. Curr Opin Hematol. 2018;25(5):373–381. doi:10.1097/MOH.0000000000000447.
  • Semple JW, Rebetz J, Maouia A, et al. An update on the pathophysiology of immune thrombocytopenia. Curr Opin Hematol. 2020;27(6):423–429. doi:10.1097/MOH.0000000000000612.
  • Nelson VS, Jolink A-TC, Amini SN, et al. Platelets in ITP: victims in charge of their own fate? Cells. 2021;10(11):3235. doi:10.3390/cells10113235.
  • Nishimoto T, Kuwana M. CD4 + CD25 + Foxp3+ regulatory T cells in the pathophysiology of immune thrombocytopenia. Semin Hematol. 2013;50 (Suppl 1):S43–S49. doi:10.1053/j.seminhematol.2013.03.018.
  • Audia S, Samson M, Guy J, et al. Immunologic effects of rituximab on the human spleen in immune thrombocytopenia. Blood. 2011;118(16):4394–4400. doi:10.1182/blood-2011-03-344051.
  • Oray M, Abu Samra K, Ebrahimiadib N, et al. Long-term side effects of glucocorticoids, Expert. Expert Opin Drug Saf. 2016;15(4):457–465. doi:10.1517/14740338.2016.1140743.
  • Seguro LPC, Rosario C, Shoenfeld Y. Long-term complications of past glucocorticoid use. Autoimmun Rev. 2013;12(5):629–632. doi:10.1016/j.autrev.2012.12.002.
  • Ghanima W, Khelif A, Waage A, et al. Rituximab as second-line treatment for adult immune thrombocytopenia (the RITP trial): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2015;385(9978):1653–1661. doi:10.1016/S0140-6736(14)61495-1.
  • Zhang J, Ruan Y, Shen Y, et al. Low dose IL-2 increase regulatory T cells and elevate platelets in a patient with immune thrombocytopenia. Cytometry B Clin Cytom. 2018;94(3):400–404. doi:10.1002/cyto.b.21494.
  • Zhang J, Ruan Y, Xu X, et al. Therapeutic potential of low-dose IL-2 in immune thrombocytopenia: An analysis of 3 cases. Cytometry B Clin Cytom. 2018;94(3):428–433. doi:10.1002/cyto.b.21601.
  • Miao M, Li Y, Huang B, et al. Hypomyopathic Dermatomyositis with Refractory Dermatitis Treated by Low-dose IL-2. Dermatol Ther (Heidelb). 2020;10(5):1181–1184. doi:10.1007/s13555-020-00421-8.
  • Long H, Liao J, Yang M, et al. Low-dose interleukin-2: A potential treatment for pemphigus vulgaris. Autoimmun Rev. 2021;20(10):102906. doi:10.1016/j.autrev.2021.102906.
  • Deng Y, Chang C, Lu Q. The inflammatory response in psoriasis: a comprehensive review. Clin Rev Allergy Immunol. 2016;50(3):377–389. doi:10.1007/s12016-016-8535-x.
  • Qiao Z, Zhao W, Liu Y, et al. Low-dose interleukin-2 For psoriasis therapy based on the regulation of Th17/Treg cell balance in peripheral blood. Inflammation. 2023; doi:10.1007/s10753-023-01883-6.
  • Gibson PG, Qin L, Puah SH. COVID-19 acute respiratory distress syndrome (ARDS): clinical features and differences from typical pre-COVID-19 ARDS. Med J Aust. 2020;213(2):54–56.e1. doi:10.5694/mja2.50674.
  • Dhawan M, Rabaan AA, Alwarthan S, et al. Regulatory T cells (Tregs) and COVID-19: unveiling the mechanisms, and therapeutic potentialities with a special focus on long COVID. Vaccines (Basel). 2023;11(3):699. doi:10.3390/vaccines11030699.
  • Alahyari S, Rajaeinejad M, Jalaeikhoo H, et al. Regulatory T Cells in immunopathogenesis and severity of COVID-19: a systematic review. Arch Iran Med. 2022;25(2):127–132. doi:10.34172/aim.2022.22.
  • Ding Q, Liu G-Q, Zeng Y-Y, et al. Role of IL-17 in LPS-induced acute lung injury: an in vivo study. Oncotarget. 2017;8(55):93704–93711. doi:10.18632/oncotarget.21474.
  • Kim DI, Song M-K, Lee K. Diesel exhaust particulates enhances susceptibility of LPS-induced acute lung injury through upregulation of the IL-17 cytokine-derived TGF-β1/Collagen I expression and activation of NLRP3 inflammasome signaling in mice. Biomolecules. 2021;11(1):67. doi:10.3390/biom11010067.
  • Zhou P, Chen J, He J, et al. Low-dose IL-2 therapy invigorates CD8+ T cells for viral control in systemic lupus erythematosus. PLoS Pathog. 2021;17(10):e1009858. doi:10.1371/journal.ppat.1009858.
  • Humrich JY, Von Spee-Mayer C, Siegert E, et al. Rapid induction of clinical remission by low-dose interleukin-2 in a patient with refractory SLE. Ann Rheum Dis. 2015;74(4):791–792. doi:10.1136/annrheumdis-2014-206506.
  • Todd JA, Evangelou M, Cutler AJ, et al. Regulatory T cell responses in participants with type 1 diabetes after a single dose of interleukin-2: A non-randomised, open label, adaptive dose-finding trial. PLoS Med. 2016;13(10):e1002139. doi:10.1371/journal.pmed.1002139.
  • Seelig E, Howlett J, Porter L, et al. The DILfrequency study is an adaptive trial to identify optimal IL-2 dosing in patients with type 1 diabetes. JCI Insight. 2018;3(19):e99306. doi:10.1172/jci.insight.99306.
  • Whangbo JS, Nikiforow S, Kim HT, et al. A phase 1 study of donor regulatory T-cell infusion plus low-dose interleukin-2 for steroid-refractory chronic graft-vs-host disease. Blood Adv. 2022;6(21):5786–5796. doi:10.1182/bloodadvances.2021006625.
  • Zhang X, Miao M, Zhang R, et al. Efficacy and safety of low-dose interleukin-2 in combination with methotrexate in patients with active rheumatoid arthritis: a randomized, double-blind, placebo-controlled phase 2 trial. Sig Transduct Target Ther. 2022;7(1):67. doi:10.1038/s41392-022-00887-2.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.