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

Editorial

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

The reason for the disappointing results came to light some years ago. IL-2 is crucial, not only for the expansion of effector T cells (Teff), but also for the expansion of regulatory T cells (Tregs), lymphocytes that are able to inhibit the activation/expansion of Teff (Boymanand Sprent, 2012; Liao et al., 2013; Waldmann, 2006). Indeed, more recent studies attempted to use IL-2 to repress the immune response in patients with autoimmune 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 clinical utility. Delivery of the cytokine can either ameliorate or exacerbate the disease depending on several factors including genetics and epigenetics, immune system maturation, disease activity and drug dosage and administration schedule. In this context, a key question is if it is possible to decouple the immunostimulatory and immunosuppressive effects of IL-2.

In the last 10 years, some members of the Tumour Necrosis Factor (TNF) super family have been demonstrated as co-stimulatory molecules. In particular, triggering OX40 (CD134, TNFRSF4), 4-1BB (CD137, TNFRSF9) and glucocorticoid-induced TNFR-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 on Tregs inhibits their activity (Voo et al., 2013; Bianchini et al., 2011; Ronchetti et al., 2004) and GITR has pro-inflammatory activity in several murine models (Nocentini and Riccardi, 2009; Galuppo et al., 2011;Ronchetti et al., 2011). GITR-mediated immune system stimulation in tumours can lead to their clearance in murine models and is under phase I study in patients with melanoma (Nocentini etal., 2012; 2015). However, the long-term effects of GITR triggering by anti-GITR Ab are unknown.

Like IL-2, GITR triggering also favours Treg expansion with 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’s immunostimulatory and immunosuppressive effects with smart drugs?

The stakes are high. Currently used immunosuppressive treatments are able to control autoimmune disease in many cases, with attenuated inflammation and symptom improvements. However, disease progresses during treatment in a high percentage of patients, even more so when drug treatment is halted (e.g., due to adverse effects). If new treatments could stably expand the Treg population in these patients, it could lead to long-term or even permanent remission.

In the last 10 years, encouraging results in mouse models seem to indicate that we may be able to control the kind of the effect. Studies using IL-2 complexed with two antibodies (Abs) demonstrated that IL-2’s effects could be directed towards one cell type. In particular, IL-2 conjugated with JES6-1 Ab preferentially induces Treg cell proliferation whereas IL-2 conjugated with S4B6 Ab preferentially induces Teff proliferation (Boyman etal., 2006). Spangler et al. (2015) recently characterized IL-2/JES6-1 and IL-2/S4B6 complexes and demonstrated that JES6-1 Ab blocks the interaction between IL-2/IL-2Rβ and IL-2/IL-2Rγ and lowers the affinity of IL-2 for IL-2Rα. Therefore, only those cells that express high levels of IL-2Rα (i.e., Tregs) are activated by the IL-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 reveal the possibility of using a similar strategy in humans.

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

Conclusion

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

Acknowledgement

The authors wish to express their gratitude to the people of their laboratory who have studied and are studying the role of GITR in autoimmune diseases (Luigi Cari, Erika Ricci, Maria Grazia Petrillo, Rodolfo Bianchini and Simona Ronchetti) and people of other groups with which we are actively cooperating.

Funding Information

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

Author’s Contributions

Giuseppe Nocentini: Participated in pointing out the main message of the editorial and wrote the manuscript.
Graziella Migliorati: Participated in pointing out the main message of the editorial and approved the final version of the manuscript.
Carlo Riccardi: Participated in pointing out the main message of the editorial, discussed and revised the manuscript and approved the final version of the manuscript.

Ethics

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

References

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

DOI: 10.1093/rheumatology/ket179

Bianchini, R., O. Bistoni, A. Alunno, M.G. Petrillo and S. 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 role of 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. Selective stimulation 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--unanswered questions 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) is critical 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. Identification of regulatory T cells in systemic lupus erythematosus. Autoimmun. Rev., 8:426-430.

DOI:10.1016/j.autrev.2009.01.004

Hartemann, A., G. Bensimon, C.A. Payan, S. Jacqueminet and 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 autologous lymphokine-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, tolerance and 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 for acute 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 in patients 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 expansion of 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 and inflammation. 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 et al., 2014. Expansion of regulatory GITR⁺CD25^low/-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 of WO2015026684A1. Expert Opin Ther Pat. Submitted.

Petrillo, M.G., S. Ronchetti, E. Ricci, A. Alunno and R.Gerli, 2015. GITR+ regulatory T cells in the treatment 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 Vs sorafenib alone in metastatic renal cell carcinoma: The ROSORC trial. Br. J. Cancer, 104: 1256-1261.

DOI:10.1038/bjc.2011.103

Ronchetti, S., E. Ricci, M.G. Petrillo, L. Cari and G. Migliorati et al., 2015. Glucocorticoid-induced tumour necrosis factor receptor-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 and P. Sportoletti et al., 2011. Glucocorticoid-Induced TNFR family Related gene (GITR)enhances dendritic cell activity. Immunol. Lett., 135: 24-33.

DOI:10.1016/j.imlet.2010.09.008

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 receptor superfamily, 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 cell subset potentiation through distinct conformational mechanisms. Immunity, 42: 815-825.

DOI:10.1016/j.immuni.2015.04.015

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 and regulatory 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 regulatory T cell defects in patients with systemic lupus erythematosus. Ann. Rheum. Dis.

DOI:10.1136/annrheumdis-2015-207776

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 and block 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.

DOI:10.1038/nri1901

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