American Journal of Pharmacology and Toxicology

Are we Able to Harness the Immunomodulatory Power of Cytokines for Novel Autoimmune Disease Treatments?

Giuseppe Nocentini, Graziella Migliorati and Carlo Riccardi

DOI : 10.3844/ajptsp.2015.37.39

American Journal of Pharmacology and Toxicology

Volume 10, Issue 2

Pages 37-39


Since the end of the 1970s, interleukin 2 (IL-2) has been known as a keyplayer in T cell expansion/activation (Watsonet al., 1980). In the late1980s, some groups used IL-2 to stimulate the immune systems of tumour patients(Jacobs et al., 1986). The idea seemed brilliant and severalattempts were made, but the results were disappointing (Lim et al., 1992; Procopio et al., 2011). Nowadays, isdifficult to find IL-2 as a first-line tumour treatment.

The reason for thedisappointing results came to light some years ago. IL-2 is crucial, not onlyfor the expansion of effector T cells (Teff), but also for the expansion ofregulatory T cells (Tregs), lymphocytes that are able to inhibit theactivation/expansion of Teff (Boymanand Sprent, 2012; Liao et al., 2013; Waldmann, 2006). Indeed, more recentstudies attempted to use IL-2 to repress the immune response in patients withautoimmune disorders and graft-versus-host disease (von Spee-Mayer et al., 2015;Hartemann et al., 2013; Matsuoka et al., 2013). However, IL-2’sparadoxical effects on immune cell homeostasis have limited its clinicalutility. Delivery of the cytokine can eitherameliorate or exacerbate the disease depending on several factors includinggenetics and epigenetics, immune system maturation, disease activity and drugdosage and administration schedule. In this context, a key question is if it ispossible to decouple the immunostimulatory and immunosuppressive effects ofIL-2.

In the last 10 years,some members of the Tumour Necrosis Factor (TNF) super family have beendemonstrated as co-stimulatory molecules. In particular, triggering OX40(CD134, TNFRSF4), 4-1BB (CD137, TNFRSF9) and glucocorticoid-inducedTNFR-related protein (GITR; CD357, TNFRSF18) together with T Cell Receptor (TCR)favours CD4+ and CD8+ T cell proliferation (Kober etal., 2008; Croft, 2014;Watts, 2005; Nocentini et al., 2012; Ronchetti et al., 2007). Furthermore, triggering OX-40 and GITR onTregs inhibits their activity (Voo et al., 2013; Bianchini et al., 2011; Ronchetti et al., 2004) and GITR haspro-inflammatory activity in several murine models (Nocentini and Riccardi, 2009; Galuppo et al., 2011;Ronchetti et al., 2011). GITR-mediatedimmune system stimulation in tumours can lead to their clearance in murinemodels and is under phase I study in patients with melanoma (Nocentini etal., 2012; 2015). However, the long-term effects of GITR triggeringby anti-GITR Ab are unknown.

Like IL-2, GITR triggering also favours Treg expansionwith immunosuppressive effects in transgenic murine models (van Olffen et al., 2009; Carrier et al.,2012). Once again the question is: Is it possible to decouple GITR’simmunostimulatory and immunosuppressive effects with smart drugs?

The stakes are high. Currently used immunosuppressivetreatments are able to control autoimmune disease in many cases, withattenuated inflammation and symptom improvements. However, disease progresses duringtreatment in a high percentage of patients, even more so when drug treatment ishalted (e.g., due to adverse effects). If new treatments could stably expandthe Treg population in these patients, it could lead to long-term or evenpermanent remission.

In the last 10 years,encouraging results in mouse models seem to indicate that we may be able tocontrol the kind of the effect. Studies using IL-2 complexed with twoantibodies (Abs) demonstrated that IL-2’s effects could be directed towards onecell type. In particular, IL-2 conjugatedwith JES6-1 Ab preferentially induces Treg cell proliferation whereas IL-2conjugated with S4B6 Ab preferentially induces Teff proliferation (Boyman etal., 2006). Spangler et al. (2015) recently characterized IL-2/JES6-1 and IL-2/S4B6 complexesand demonstrated that JES6-1 Ab blocks the interaction between IL-2/IL-2Rβ andIL-2/IL-2Rγ and lowers the affinity of IL-2 for IL-2Rα. Therefore, only thosecells that express high levels of IL-2Rα (i.e., Tregs) are activated by theIL-2/JES6-1 complex. Conversely, IL-2/S4B6 complex favours IL-2/IL-2Rβinteraction, stimulating cells that express high levels of IL-2Rβ (i.e., Teff).Although studies with JES6-1 and S4B6 have been performed in mice, they revealthe possibility of using a similar strategy in humans.

Studies on murine GITR have demonstrated that different antibodies canpreferentially stimulate Teff or Treg expansion/activation so that the formercan favour tumour rejection (Nishioka et al., 2008). The rationale forthe unique activities of these antibodies is not clear, but data demonstratethat GITR triggering by different molecules can preferentially co-stimulateeither Teff or Tregs (Petrillo et al., 2015). Moreover, patients with autoimmune diseases show amilder phenotype when GITR+ Tregs are expanded, suggesting that GITRis crucial in Treg expansion, which can counteract autoimmune diseaseprogression (Alunno et al., 2013; Nocentini et al., 2014; Ronchetti et al., 2015; Gerli et al., 2009).


We firmly believe that in the near future it will be possible to treatpatients with autoimmune diseases in a way that specifically facilitates Tregexpansion and allows long-term disease remission. The last mile must beurgently walked.


The authors wish to express their gratitude to the people of theirlaboratory who have studied and are studying the role of GITR in autoimmunediseases (Luigi Cari, Erika Ricci, Maria Grazia Petrillo, Rodolfo Bianchini andSimona Ronchetti) and people of other groups with which we are activelycooperating.

Funding Information

This work was supported by Associazione Italiana per laRicerca sul Cancro IG-14291 to Carlo Riccardi.

Author’s Contributions

Giuseppe Nocentini: Participatedin pointing out the main message of the editorial and wrote the manuscript.

Graziella Migliorati: Participatedin pointing out the main message of the editorial and approved the finalversion of the manuscript.

Carlo Riccardi: Participated in pointing out the main message of theeditorial, discussed and revised the manuscript and approved the final versionof the manuscript.


The authors declare they do not have any conflict ofinterest concerning the matter of the Editorial.


Alunno, A., M.G. Petrillo, G.Nocentini, O. Bistoni and E. Bartoloni etal., 2013. Characterization of a new regulatory CD4+ T cell subset inprimary Sjögren’s syndrome. Rheumatology,52: 1387-1396.

        DOI: 10.1093/rheumatology/ket179

Bianchini, R., O. Bistoni, A. Alunno, M.G. Petrillo andS. Ronchetti et al., 2011. CD4+CD25lowGITR+ cells: A novel humanCD4+ T-cell population with regulatory activity. Eur. J. Immunol., 41:2269-2278.

        DOI: 10.1002/eji.201040943

Boyman, O. and J. Sprent, 2012. The roleof interleukin-2 during homeostasis and activation of the immune system. Nat. Rev. Immunol., 12: 180-190.

        DOI: 10.1038/nri3156

Boyman, O., M. Kovar, M.P.Rubinstein, C.D. Surh and J. Sprent, 2006. Selectivestimulation of T cell subsets with antibody-cytokine immune complexes. Science, 311: 1924-1927.

        DOI: 10.1126/science.1122927

Carrier, Y., M.J. Whitters, J.S. Miyashiro, T.P.LaBranche and H.E. Ramon et al.,2012. Enhanced GITR/GITRL interactions augmentIL-27 expression and induce IL-10-producing Tr-1 like cells. Eur. J. Immunol., 42: 1393-1404.

        DOI: 10.1002/eji.201142162

Croft, M., 2014. The TNF family in T cell differentiation and function--unansweredquestions and future directions. Semin.Immunol., 26: 183-190.

        DOI: 10.1016/j.smim.2014.02.005

Galuppo, M., G. Nocentini, E. Mazzon, S. Ronchetti and E.Esposito et al., 2011. The glucocorticoid-induced TNF receptor family-related protein (GITR) iscritical to the development of acute pancreatitis in mice. Br. J. Pharmacol., 162: 1186-1201.

        DOI: 10.1111/j.1476-5381.2010.01123.x

Gerli, R., G. Nocentini, A. Alunno, E.B. Bocci and R.Bianchini et al., 2009. Identificationof regulatory T cells in systemic lupus erythematosus. Autoimmun. Rev., 8:426-430.


Hartemann, A., G. Bensimon, C.A. Payan, S. Jacqueminetand O. Bourron et al., 2013. Low-dose interleukin 2 in patients with type 1diabetes: A phase 1/2 randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol., 1: 295-305.

        DOI: 10.1016/S2213-8587(13)70113-X

Jacobs, S.K., D.J. Wilson, P.L. Kornblith and E.A.Grimm, 1986. Interleukin-2 or autologouslymphokine-activated killer cell treatment of malignant glioma: Phase I trial. Cancer Res., 46: 2101-2104.

Kober, J., J. Leitner, C. Klauser, R. Woitek and O.Majdic et al., 2008. The capacity of the TNF family members 4-1BBL, OX40L,CD70, GITRL, CD30L and LIGHT to costimulate human T cells. Eur. J. Immunol., 38: 2678-2688.

        DOI: 10.1002/eji.200838250

Liao, W., J.X. Lin and W.J. Leonard, 2013. Interleukin-2 at the crossroads of effector responses, toleranceand immunotherapy. Immunity, 38: 13-25.

        DOI: 10.1016/j.immuni.2013.01.004

Lim, S.H., A.C. Newland, S. Kelsey, A. Bell and E.Offerman et al., 1992. Continuous intravenous infusion of high-dose recombinant interleukin-2 foracute myeloid leukaemia--a phase II study. Cancer Immunol. Immunother., 34: 337-342.

        DOI: 10.1007/BF01741555

Matsuoka, K., J. Koreth, H.T. Kim, G. Bascug and S.McDonough et al., 2013. Low-dose interleukin-2 therapy restores regulatory T cell homeostasis inpatients with chronic graft-versus-host disease. Sci. Transl. Med., 5:179-143.

        DOI: 10.1126/scitranslmed.3005265

Nishioka, T., E. Nishida, R. Iida, A. Morita and J.Shimizu, 2008. In vivo expansionof CD4+Foxp3+ regulatory T cells mediated by GITR molecules. Immunol. Lett., 121: 97-104.

        DOI: 10.1016/j.imlet.2008.09.003

Nocentini, G. and C. Riccardi, 2009. GITR: A modulator of immune response andinflammation. Adv. Exp. Med. Biol.,647: 156-173.

        DOI: 10.1007/978-0-387-89520-8_11

Nocentini, G., A. Alunno,M.G. Petrillo, O. Bistoni and E. Bartoloni etal., 2014. Expansion of regulatory GITR+CD25low/-CD4+T cells in systemic lupus erythematosus patients. Arthritis Res. Ther., 16:444.

        DOI: 10.1186/s13075-014-0444-x

Nocentini, G., S. Ronchetti, M.G. Petrillo and C.Riccardi, 2012. Pharmacological modulation of GITRL/GITR system:Therapeutic perspectives. Br. J.Pharmacol., 165:2089-2099.

        DOI: 10.1111/j.1476-5381.2011.01753.x

Nocentini, G., L. Cari, S. Ronchetti and C. Riccardi, 2015. Modulation of tumor immunity: A patent evaluation ofWO2015026684A1. Expert Opin Ther Pat.Submitted.

Petrillo, M.G., S. Ronchetti, E. Ricci, A. Alunno and R.Gerli, 2015. GITR+ regulatory T cells in thetreatment of autoimmune diseases. Autoimmun.Rev., 14: 117-126.

        DOI: 10.1016/j.autrev.2014.10.011

Procopio,G., E. Verzoni, S. Bracarda, S. Ricci and C. Sacco et al., 2011. Sorafenib with interleukin-2 Vssorafenib alone in metastatic renal cell carcinoma: The ROSORC trial. Br. J. Cancer, 104: 1256-1261.


Ronchetti,S., E. Ricci, M.G. Petrillo, L. Cari and G. Migliorati et al., 2015. Glucocorticoid-induced tumour necrosis factorreceptor-related protein: A key marker of functional regulatory T cells. J. Immunol. Res., 2015: 171520.

        DOI: 10.1155/2015/171520

 Ronchetti, S., G. Nocentini, M.G. Petrillo, R. Bianchini andP. Sportoletti et al., 2011. Glucocorticoid-Induced TNFR family Related gene (GITR)enhances dendritic cell activity. Immunol.Lett., 135: 24-33.


Ronchetti,S., G. Nocentini, R. Bianchini, L.T. Krausz and G. Migliorati et al., 2007. Glucocorticoid-induced TNFR-related protein lowers the threshold of CD28costimulation in CD8+ T cells. J.Immunol., 179: 5916-5926.

        DOI: 10.4049/?jimmunol.179.9.5916

Ronchetti,S., O. Zollo, S. Bruscoli, M. Agostini and R. Bianchini et al., 2004. Frontline: GITR, a member of the TNF receptorsuperfamily, is costimulatory to mouse T lymphocyte subpopulations. Eur. J. Immunol., 34: 613-622.

        DOI: 10.1002/eji.200324804

Spangler, J.B., J. Tomala, V.C. Luca, K.M. Jude and S. Dong et al., 2015. Antibodies to interleukin-2 elicit selective T cellsubset potentiation through distinct conformational mechanisms. Immunity, 42: 815-825.


van Olffen, R.W., N. Koning, K.P. van Gisbergen, F.M.Wensveen and R.M. Hoek et al., 2009. GITR triggering induces expansion of both effector andregulatory CD4+ T cells in vivo. J. Immunol., 182: 7490-7500.

        DOI: 10.4049/?jimmunol.0802751

von Spee-Mayer, C., E. Siegert, D. Abdirama, A. Rose and A.Klaus et al., 2015. Low-dose interleukin-2 selectively corrects regulatoryT cell defects in patients with systemic lupus erythematosus. Ann. Rheum. Dis.


Voo,K.S., L. Bover, M.L. Harline, L.T. Vien and V. Facchinetti et al., 2013. Antibodies targeting human OX40 expand effector T cells andblock inducible and natural regulatory T cell function. J. Immunol., 191:3641-3650.

        DOI: 10.4049/?jimmunol.1202752

Waldmann,T.A., 2006. The biology of interleukin-2 and interleukin-15:Implications for cancer therapy and vaccine design. Nat. Rev. Immunol., 6:595-601.


Watson, J., D. Mochizuki and S. Gillis, 1980. T-cell growth factors: Interleukin 2. Immunol. Today, 1: 113-117.

Watts, T.H., 2005.TNF/TNFR family members in costimulation of T cell responses. Annu. Rev. Immunol., 23: 23-68.

       DOI: 10.1146/annurev.immunol.23.021704.115839


© 2015 Giuseppe Nocentini, Graziella Migliorati and Carlo Riccardi. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.