G Model YPHRS 2807 1–2
ARTICLE IN PRESS Pharmacological Research xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Pharmacological Research journal homepage: www.elsevier.com/locate/yphrs
1
Editorial
2
Novel therapies for T1D on the horizon
3
4 5
Keywords:
6
Type 1 diabetes NOD mice Immunotherapy Stem cells Immunosuppression
7 8 9 10 11
12Q3 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48
Although many progresses have been made in the treatment of hyperglycemia and management of diabetic complications, a feasible and safe cures capable of normalizing hyperglycemia in individuals with type 1 diabetes (T1D) is needed [1–4]. Being conceived as a progressive autoimmune disease [5], T1D is characterized by an autoreactive T cells-mediated autoimmune and selective destruction of insulin producing -cells [6]. The prevalence of T1D has increased by 2–5% worldwide and reached approximately one every 300 in US by 18 years of age [7]. Recent studies conducted by different and independent groups suggested that T1D is still associated with an increased mortality risk [8], albeit an overall improvement of quality of life was observed after the introduction of more accurate insulin therapy regimen and of new insulin analogues, as revealed by a significant decrease of diabetic ketoacidosis-associated mortality [9]. The introduction of intensive insulin therapy in large clinical trials (e.g.; the DCCT study), established the proof-of-concept that a better and strict management of T1D-associated hyperglycemia leads to the reduction of major diabetic complications, with a decrease of the risk of developing diabetic retinopathy by 76%, nephropathy by 50% and neuropathy by 60% [10]. Yet, whether mortality in T1D is improved by intensive insulin therapy remains still controversial, since numerous studies claimed recently that the mortality rate associated to T1D is still high despite the whole progress in the management of glycometabolic control and in the treatment of cardiovascular risk factors [11]. This striving point was nicely pointed out in a recent published study by Lind and colleagues, in which the relationship between all-cause and cardiovascular associated mortality and improved glycemic levels was analyzed in individuals with T1D compared to their peers controls without T1D [8]. Authors reported that T1D individuals with an excellent glycemic control (as revealed by HbA1c < 6.9%) were exposed to a two fold increased risk of overall mortality and a threefold CVD-associated mortality risk [8,11]. This surprising finding ascertains that improving glycemic control is not enough, and that in order to achieve the best possible option in the management of the disease, we must identify other risk factors, search for biomarkers of disease progression and potentially
look for therapy capable of inducing the complete remission of T1D [12,13]. Recently, Livingstone and his collaborators published new data regarding life expectancy for adults with T1D and revealed that women and men at the age of 20 years old may expect to live 12.9 and 11.1 years respectively fewer than their corresponding healthy controls. Even those T1D individuals with a preserved renal function may face an estimated 8-year reduction of life expectancy [14]; this was partially corrected by Orchard and colleagues, that reported a similar mortality rate in T1D with no renal associated disease and individuals free from T1D. Furthermore, Orchard et al. [15] showed that the overall mortality associated risk in the intensive insulin therapy-treated group was only modestly reduced as compared with the conventional therapy-treated group in an observational long-term follow up of a selective North American cohort who participated in the DCCT and EDIC study. Authors observed a modestly lower all-cause mortality rate with a small absolute reduction risk as about 1/100 patient-years after 6.5 years of initial intensive diabetes therapy [15]. All together, these results underscore the big challenge that still remains in order to strive against T1D, the improvement of glycometabolic control through intensification of insulin therapy is one of the targets of the fight against T1D and may actually result in the increase in life threatening events due to the augmented incidence of hypoglycemia [16]. In this special issue of Pharmacological research we are exploring the state-of-the-art of novel therapies currently under evaluation for T1D individuals. Nowadays therapeutic options for T1D include islet and pancreas transplantation [17,18], which could restore normoglycemia at different degrees and for a different period of time without any resurgent risk of hypoglycemia [17,19] and may prevent, halt, or reverse the development or progression of secondary diabetes complications [18,20,21]. However, the high rate of immunological graft failure with both procedure, the shortage of donors [22], the absence of reliable and strong markers of rejection [23] and the risk of chronic long-term immosuppressive regimen, limited the establishment of pancreas and islet transplantation as alternatives options for diabetes’ treatments [18,24]. The hype related to the successful preclinical studies in the NOD mice, was unfortunately accompanied by the failure to translate these immunotherapies to humans [2]. The main differences reside in the heterogeneity of the disease in humans, the need for a better optimization of the dosing and issues related with the timing of intervention which needs to be better explored [2,25]. Novel pathways involved in the onset of T1D have been identified thanks to the use of NOD mice [26–29], that led to the creation of few approaches capable of reverting hyperglycemia in NOD mice [30–35]. Novel
http://dx.doi.org/10.1016/j.phrs.2015.03.019 1043-6618/© 2015 Published by Elsevier Ltd.
Please cite this article in press as: M. Ben Nasr, P. Fiorina, Novel therapies for T1D on the horizon, Pharmacol Res (2015), http://dx.doi.org/10.1016/j.phrs.2015.03.019
49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93
G Model YPHRS 2807 1–2
Editorial / Pharmacological Research xxx (2015) xxx–xxx
2 94 95 96 97 98 99 100 101 102 103
ARTICLE IN PRESS
and unexpected pathways are under investigation for their role either in alloimmune response or in inflammation [30,36–38]. The use of stem cells recently held great promise for the cure of T1D; indeed stem-cell-based therapy in T1D can halt the autoimmune response generated against insulin-producing cells [31,39,40] and potentially can sustain -cell replenishment [41,42]. The use of regulatory T cells, may appear another exciting field to be explore as well, once solved the issue of poor half-life and stability [43,44]. This special issue focuses on the different approaches tested so far for the modulation of the immune response in patients with T1D, shedding a light of hope into the future of this devastating disease.
[25] [26] [27] [28] [29] [30]
104
[31] 105
References
[1] S. Lord, C. Greenbaum, Disease modifying therapies in type 1 diabetes: where 107 Q4 have we been, and where are we going? Pharmacol. Res. (2015) (in press). 108 [2] M. Ben Nasr, F. D’Addio, V. Usuelli, S. Tezza, R. Abdi, P. Fiorina, The rise, fall, and 109 resurgence of immunotherapy in type 1 diabetes, Pharmacol. Res. (2014). 110 [3] E.B. Tsai, N.A. Sherry, J.P. Palmer, K.C. Herold, The rise and fall of insulin secretion 111 in type 1 diabetes mellitus, Diabetologia 49 (2006) 261–270. 112 [4] J.S. Skyler, The year in immune intervention for type 1 diabetes, Diab. Technol. 113 Ther. 15 (Suppl 1) (2013) S88–S95. 114 [5] G.S. Eisenbarth, Type I diabetes mellitus. A chronic autoimmune disease, N. 115 Engl. J. Med. 314 (1986) 1360–1368. 116 [6] Diagnosis and classification of diabetes mellitus, Diab. Care 32 (Suppl. 1) (2009) 117 S62–S67. 118 [7] Z. Tao, A. Shi, J. Zhao, Epidemiological perspectives of diabetes, Cell Biochem. 119 Biophys. (2015). 120 [8] M. Lind, A.M. Svensson, M. Kosiborod, et al., Glycemic control and excess mor121 tality in type 1 diabetes, N. Engl. J. Med. 371 (2014) 1972–1982. 122 [9] M. Katz, L. Laffel, Mortality in type 1 diabetes in the current era: two steps 123 forward, one step backward, JAMA 313 (2015) 35–36. 124 [10] D.M. Nathan, M. Bayless, P. Cleary, et al., Diabetes control and complications 125 trial/epidemiology of diabetes interventions and complications study at 30 126 years: advances and contributions, Diabetes 62 (2013) 3976–3986. 127 [11] J.K. Snell-Bergeon, D.M. Maahs, Diabetes: elevated risk of mortality in type 1 128 diabetes mellitus, Nat. Rev. Endocrinol. 11 (2015) 136–138. 129 [12] G.V. Zuccotti, A. Scaramuzza, Modern clinical management helps reducing the 130 impact of type 1 diabetes in children’s, Pharmacol. Res. (2015) (in press). 131 [13] V. Usuelli, E. La Rocca, Novel approaches for type 1 diabetic complications, 132 Pharmacol. Res. (2015) (in press). 133 [14] S.J. Livingstone, D. Levin, H.C. Looker, et al., Estimated life expectancy in a 134 Scottish cohort with type 1 diabetes, 2008–2010, JAMA 313 (2015) 37–44. 135 [15] T.J. Orchard, D.M. Nathan, B. Zinman, et al., Association between 7 years of 136 intensive treatment of type 1 diabetes and long-term mortality, JAMA 313 137 (2015) 45–53. 138 [16] R.S. Weinstock, D. Xing, D.M. Maahs, et al., Severe hypoglycemia and diabetic 139 ketoacidosis in adults with type 1 diabetes: results from the T1D Exchange 140 clinic registry, J. Clin. Endocrinol. Metab. 98 (2013) 3411–3419. 141 [17] S. Tezza, M. Ben Nasr, A. Vergani, et al., Novel immunological strategies for islet 142 transplantation, Pharmacol. Res. (2014). 143 [18] P. Fiorina, A.M. Shapiro, C. Ricordi, A. Secchi, The clinical impact of islet trans144 plantation, Am. J. Transplant. 8 (2008) 1990–1997. 145 [19] P. Maffi, A. Secchi, Clinical results of islet transplantation, Pharmacol. Res. 146 (2015) (in press). 147 [20] P. Fiorina, A. Secchi, Pancreatic islet cell transplant for treatment of diabetes, 148 Endocrinol. Metab. Clin. North Am. 36 (2007) 999–1013, ix. 149 [21] R.W. Gruessner, Pancreas transplantation, Curr. Opin. Organ Transplant. 15 150 (2010) 92. 151 [22] C. Watson, The current challenges for pancreas transplantation for diabetes 152 mellitus, Pharmacol. Res. (2015) (in press). 153 [23] M. Venturini, P. Maffi, G. Querques, et al., Hepatic steatosis after islet transplan154 tation: can ultrasound predict the clinical outcomes? Pharmacol. Res. (2015) 155 (in press). 156 [24] A.C. Gruessner, 2011 update on pancreas transplantation: comprehensive trend analysis of 25,000 cases followed up over the course of twenty-four years at
[32]
106
[33] [34]
[35]
[36]
[37] [38] [39] [40]
[41] [42] [43] [44]
the International Pancreas Transplant Registry (IPTR), Rev. Diab. Stud. 8 (2011) 6–16. M.A. Atkinson, G.D. Ogle, Improving diabetes care in resource-poor countries: challenges and opportunities, Lancet Diab. Endocrinol. 1 (2013) 268–270. I. Guleria, M. Gubbels Bupp, S. Dada, et al., Mechanisms of PDL1-mediated regulation of autoimmune diabetes, Clin. Immunol. 125 (2007) 16–25. M.J. Ansari, P. Fiorina, S. Dada, et al., Role of ICOS pathway in autoimmune and alloimmune responses in NOD mice, Clin. Immunol. 126 (2008) 140–147. P. Fiorina, A. Vergani, S. Dada, et al., Targeting CD22 reprograms B-cells and reverses autoimmune diabetes, Diabetes 57 (2008) 3013–3024. F.S.W. Changyun Hu, Wen. Li, Type 1 diabetes and gut microbiota: friend or foe? Pharmacol. Res. (2015). A. Vergani, F. D’Addio, M. Jurewicz, et al., A novel clinically relevant strategy to abrogate autoimmunity and regulate alloimmunity in NOD mice, Diabetes 59 (2010) 2253–2264. P. Fiorina, J. Voltarelli, N. Zavazava, Immunological applications of stem cells in type 1 diabetes, Endocr. Rev. 32 (2011) 725–754. C.Y. Hu, D. Rodriguez-Pinto, W. Du, et al., Treatment with CD20-specific antibody prevents and reverses autoimmune diabetes in mice, J. Clin. Invest. 117 (2007) 3857–3867. K.C. Herold, W. Hagopian, J.A. Auger, et al., Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus, N. Engl. J. Med. 346 (2002) 1692–1698. T. Orban, B. Bundy, D.J. Becker, et al., Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial, Lancet 378 (2011) 412–419. M.J. Haller, S.E. Gitelman, P.A. Gottlieb, et al., Anti-thymocyte globulin/G-CSF treatment preserves beta cell function in patients with established type 1 diabetes, J. Clin. Invest. 125 (2015) 448–455. P. Fiorina, G. Lattuada, O. Ponari, C. Silvestrini, P. DallAglio, Impaired nocturnal melatonin excretion and changes of immunological status in ischaemic stroke patients, Lancet 347 (1996) 692–693. A. Vergani, C. Fotino, F. D’Addio, et al., Effect of the purinergic inhibitor oxidized ATP in a model of islet allograft rejection, Diabetes 62 (2013) 1665–1675. A. Vergani, F. Gatti, K.M. Lee, et al., TIM4 regulates the anti-islet Th2 alloimmune response, Cell Transplant. (2014). R. Francese, P. Fiorina, Immunological and regenerative properties of cord blood stem cells, Clin. Immunol. 136 (2010) 309–322. F. D’Addio, A. Valderrama Vasquez, M. Ben Nasr, et al., Autologous nonmyeloablative hematopoietic stem cell transplantation in new-onset type 1 diabetes: a multicenter analysis, Diabetes 63 (2014) 3041–3046. C. Schuetz, J. Markmann, Immunogenicity of ß-cells for autologous transplantation in type 1 diabetes, Pharmacol. Res. (2015) (in press). A. Pileggi, C. Fotino, Re-engineering islet cell transplantation, Pharmacol. Res. (2015) (in press). X.C. Lin, B. El Essawy, Type 1 diabetes and regulatory cells, Pharmacol. Res. (2015) (in press). N. Komatsu, K. Okamoto, S. Sawa, et al., Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis, Nat. Med. 20 (2014) 62–68.
Moufida Ben Nasr a,b Q1 Paolo Fiorina a,b,∗ a Nephrology Division, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States Q2 b Transplant Medicine, San Raffaele Hospital, Milan, Italy ∗ Corresponding
author at: Nephrology Division, Boston Children’s Hospital, Harvard Medical School, Enders Building 5th floor, Room EN511, 300 Longwood Ave., Boston, MA 02115, United States. Tel.: +1 617 919 2624; fax: +1 617 730 0365. E-mail address: paolo.fi[email protected] (P. Fiorina) Available online xxx
Please cite this article in press as: M. Ben Nasr, P. Fiorina, Novel therapies for T1D on the horizon, Pharmacol Res (2015), http://dx.doi.org/10.1016/j.phrs.2015.03.019
157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204
205 206 207 208 209 210
211 212 213 214 215 216 217
218
ARTICLE IN PRESS Pharmacological Research xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Pharmacological Research journal homepage: www.elsevier.com/locate/yphrs
1
Editorial
2
Novel therapies for T1D on the horizon
3
4 5
Keywords:
6
Type 1 diabetes NOD mice Immunotherapy Stem cells Immunosuppression
7 8 9 10 11
12Q3 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48
Although many progresses have been made in the treatment of hyperglycemia and management of diabetic complications, a feasible and safe cures capable of normalizing hyperglycemia in individuals with type 1 diabetes (T1D) is needed [1–4]. Being conceived as a progressive autoimmune disease [5], T1D is characterized by an autoreactive T cells-mediated autoimmune and selective destruction of insulin producing -cells [6]. The prevalence of T1D has increased by 2–5% worldwide and reached approximately one every 300 in US by 18 years of age [7]. Recent studies conducted by different and independent groups suggested that T1D is still associated with an increased mortality risk [8], albeit an overall improvement of quality of life was observed after the introduction of more accurate insulin therapy regimen and of new insulin analogues, as revealed by a significant decrease of diabetic ketoacidosis-associated mortality [9]. The introduction of intensive insulin therapy in large clinical trials (e.g.; the DCCT study), established the proof-of-concept that a better and strict management of T1D-associated hyperglycemia leads to the reduction of major diabetic complications, with a decrease of the risk of developing diabetic retinopathy by 76%, nephropathy by 50% and neuropathy by 60% [10]. Yet, whether mortality in T1D is improved by intensive insulin therapy remains still controversial, since numerous studies claimed recently that the mortality rate associated to T1D is still high despite the whole progress in the management of glycometabolic control and in the treatment of cardiovascular risk factors [11]. This striving point was nicely pointed out in a recent published study by Lind and colleagues, in which the relationship between all-cause and cardiovascular associated mortality and improved glycemic levels was analyzed in individuals with T1D compared to their peers controls without T1D [8]. Authors reported that T1D individuals with an excellent glycemic control (as revealed by HbA1c < 6.9%) were exposed to a two fold increased risk of overall mortality and a threefold CVD-associated mortality risk [8,11]. This surprising finding ascertains that improving glycemic control is not enough, and that in order to achieve the best possible option in the management of the disease, we must identify other risk factors, search for biomarkers of disease progression and potentially
look for therapy capable of inducing the complete remission of T1D [12,13]. Recently, Livingstone and his collaborators published new data regarding life expectancy for adults with T1D and revealed that women and men at the age of 20 years old may expect to live 12.9 and 11.1 years respectively fewer than their corresponding healthy controls. Even those T1D individuals with a preserved renal function may face an estimated 8-year reduction of life expectancy [14]; this was partially corrected by Orchard and colleagues, that reported a similar mortality rate in T1D with no renal associated disease and individuals free from T1D. Furthermore, Orchard et al. [15] showed that the overall mortality associated risk in the intensive insulin therapy-treated group was only modestly reduced as compared with the conventional therapy-treated group in an observational long-term follow up of a selective North American cohort who participated in the DCCT and EDIC study. Authors observed a modestly lower all-cause mortality rate with a small absolute reduction risk as about 1/100 patient-years after 6.5 years of initial intensive diabetes therapy [15]. All together, these results underscore the big challenge that still remains in order to strive against T1D, the improvement of glycometabolic control through intensification of insulin therapy is one of the targets of the fight against T1D and may actually result in the increase in life threatening events due to the augmented incidence of hypoglycemia [16]. In this special issue of Pharmacological research we are exploring the state-of-the-art of novel therapies currently under evaluation for T1D individuals. Nowadays therapeutic options for T1D include islet and pancreas transplantation [17,18], which could restore normoglycemia at different degrees and for a different period of time without any resurgent risk of hypoglycemia [17,19] and may prevent, halt, or reverse the development or progression of secondary diabetes complications [18,20,21]. However, the high rate of immunological graft failure with both procedure, the shortage of donors [22], the absence of reliable and strong markers of rejection [23] and the risk of chronic long-term immosuppressive regimen, limited the establishment of pancreas and islet transplantation as alternatives options for diabetes’ treatments [18,24]. The hype related to the successful preclinical studies in the NOD mice, was unfortunately accompanied by the failure to translate these immunotherapies to humans [2]. The main differences reside in the heterogeneity of the disease in humans, the need for a better optimization of the dosing and issues related with the timing of intervention which needs to be better explored [2,25]. Novel pathways involved in the onset of T1D have been identified thanks to the use of NOD mice [26–29], that led to the creation of few approaches capable of reverting hyperglycemia in NOD mice [30–35]. Novel
http://dx.doi.org/10.1016/j.phrs.2015.03.019 1043-6618/© 2015 Published by Elsevier Ltd.
Please cite this article in press as: M. Ben Nasr, P. Fiorina, Novel therapies for T1D on the horizon, Pharmacol Res (2015), http://dx.doi.org/10.1016/j.phrs.2015.03.019
49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93
G Model YPHRS 2807 1–2
Editorial / Pharmacological Research xxx (2015) xxx–xxx
2 94 95 96 97 98 99 100 101 102 103
ARTICLE IN PRESS
and unexpected pathways are under investigation for their role either in alloimmune response or in inflammation [30,36–38]. The use of stem cells recently held great promise for the cure of T1D; indeed stem-cell-based therapy in T1D can halt the autoimmune response generated against insulin-producing cells [31,39,40] and potentially can sustain -cell replenishment [41,42]. The use of regulatory T cells, may appear another exciting field to be explore as well, once solved the issue of poor half-life and stability [43,44]. This special issue focuses on the different approaches tested so far for the modulation of the immune response in patients with T1D, shedding a light of hope into the future of this devastating disease.
[25] [26] [27] [28] [29] [30]
104
[31] 105
References
[1] S. Lord, C. Greenbaum, Disease modifying therapies in type 1 diabetes: where 107 Q4 have we been, and where are we going? Pharmacol. Res. (2015) (in press). 108 [2] M. Ben Nasr, F. D’Addio, V. Usuelli, S. Tezza, R. Abdi, P. Fiorina, The rise, fall, and 109 resurgence of immunotherapy in type 1 diabetes, Pharmacol. Res. (2014). 110 [3] E.B. Tsai, N.A. Sherry, J.P. Palmer, K.C. Herold, The rise and fall of insulin secretion 111 in type 1 diabetes mellitus, Diabetologia 49 (2006) 261–270. 112 [4] J.S. Skyler, The year in immune intervention for type 1 diabetes, Diab. Technol. 113 Ther. 15 (Suppl 1) (2013) S88–S95. 114 [5] G.S. Eisenbarth, Type I diabetes mellitus. A chronic autoimmune disease, N. 115 Engl. J. Med. 314 (1986) 1360–1368. 116 [6] Diagnosis and classification of diabetes mellitus, Diab. Care 32 (Suppl. 1) (2009) 117 S62–S67. 118 [7] Z. Tao, A. Shi, J. Zhao, Epidemiological perspectives of diabetes, Cell Biochem. 119 Biophys. (2015). 120 [8] M. Lind, A.M. Svensson, M. Kosiborod, et al., Glycemic control and excess mor121 tality in type 1 diabetes, N. Engl. J. Med. 371 (2014) 1972–1982. 122 [9] M. Katz, L. Laffel, Mortality in type 1 diabetes in the current era: two steps 123 forward, one step backward, JAMA 313 (2015) 35–36. 124 [10] D.M. Nathan, M. Bayless, P. Cleary, et al., Diabetes control and complications 125 trial/epidemiology of diabetes interventions and complications study at 30 126 years: advances and contributions, Diabetes 62 (2013) 3976–3986. 127 [11] J.K. Snell-Bergeon, D.M. Maahs, Diabetes: elevated risk of mortality in type 1 128 diabetes mellitus, Nat. Rev. Endocrinol. 11 (2015) 136–138. 129 [12] G.V. Zuccotti, A. Scaramuzza, Modern clinical management helps reducing the 130 impact of type 1 diabetes in children’s, Pharmacol. Res. (2015) (in press). 131 [13] V. Usuelli, E. La Rocca, Novel approaches for type 1 diabetic complications, 132 Pharmacol. Res. (2015) (in press). 133 [14] S.J. Livingstone, D. Levin, H.C. Looker, et al., Estimated life expectancy in a 134 Scottish cohort with type 1 diabetes, 2008–2010, JAMA 313 (2015) 37–44. 135 [15] T.J. Orchard, D.M. Nathan, B. Zinman, et al., Association between 7 years of 136 intensive treatment of type 1 diabetes and long-term mortality, JAMA 313 137 (2015) 45–53. 138 [16] R.S. Weinstock, D. Xing, D.M. Maahs, et al., Severe hypoglycemia and diabetic 139 ketoacidosis in adults with type 1 diabetes: results from the T1D Exchange 140 clinic registry, J. Clin. Endocrinol. Metab. 98 (2013) 3411–3419. 141 [17] S. Tezza, M. Ben Nasr, A. Vergani, et al., Novel immunological strategies for islet 142 transplantation, Pharmacol. Res. (2014). 143 [18] P. Fiorina, A.M. Shapiro, C. Ricordi, A. Secchi, The clinical impact of islet trans144 plantation, Am. J. Transplant. 8 (2008) 1990–1997. 145 [19] P. Maffi, A. Secchi, Clinical results of islet transplantation, Pharmacol. Res. 146 (2015) (in press). 147 [20] P. Fiorina, A. Secchi, Pancreatic islet cell transplant for treatment of diabetes, 148 Endocrinol. Metab. Clin. North Am. 36 (2007) 999–1013, ix. 149 [21] R.W. Gruessner, Pancreas transplantation, Curr. Opin. Organ Transplant. 15 150 (2010) 92. 151 [22] C. Watson, The current challenges for pancreas transplantation for diabetes 152 mellitus, Pharmacol. Res. (2015) (in press). 153 [23] M. Venturini, P. Maffi, G. Querques, et al., Hepatic steatosis after islet transplan154 tation: can ultrasound predict the clinical outcomes? Pharmacol. Res. (2015) 155 (in press). 156 [24] A.C. Gruessner, 2011 update on pancreas transplantation: comprehensive trend analysis of 25,000 cases followed up over the course of twenty-four years at
[32]
106
[33] [34]
[35]
[36]
[37] [38] [39] [40]
[41] [42] [43] [44]
the International Pancreas Transplant Registry (IPTR), Rev. Diab. Stud. 8 (2011) 6–16. M.A. Atkinson, G.D. Ogle, Improving diabetes care in resource-poor countries: challenges and opportunities, Lancet Diab. Endocrinol. 1 (2013) 268–270. I. Guleria, M. Gubbels Bupp, S. Dada, et al., Mechanisms of PDL1-mediated regulation of autoimmune diabetes, Clin. Immunol. 125 (2007) 16–25. M.J. Ansari, P. Fiorina, S. Dada, et al., Role of ICOS pathway in autoimmune and alloimmune responses in NOD mice, Clin. Immunol. 126 (2008) 140–147. P. Fiorina, A. Vergani, S. Dada, et al., Targeting CD22 reprograms B-cells and reverses autoimmune diabetes, Diabetes 57 (2008) 3013–3024. F.S.W. Changyun Hu, Wen. Li, Type 1 diabetes and gut microbiota: friend or foe? Pharmacol. Res. (2015). A. Vergani, F. D’Addio, M. Jurewicz, et al., A novel clinically relevant strategy to abrogate autoimmunity and regulate alloimmunity in NOD mice, Diabetes 59 (2010) 2253–2264. P. Fiorina, J. Voltarelli, N. Zavazava, Immunological applications of stem cells in type 1 diabetes, Endocr. Rev. 32 (2011) 725–754. C.Y. Hu, D. Rodriguez-Pinto, W. Du, et al., Treatment with CD20-specific antibody prevents and reverses autoimmune diabetes in mice, J. Clin. Invest. 117 (2007) 3857–3867. K.C. Herold, W. Hagopian, J.A. Auger, et al., Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus, N. Engl. J. Med. 346 (2002) 1692–1698. T. Orban, B. Bundy, D.J. Becker, et al., Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial, Lancet 378 (2011) 412–419. M.J. Haller, S.E. Gitelman, P.A. Gottlieb, et al., Anti-thymocyte globulin/G-CSF treatment preserves beta cell function in patients with established type 1 diabetes, J. Clin. Invest. 125 (2015) 448–455. P. Fiorina, G. Lattuada, O. Ponari, C. Silvestrini, P. DallAglio, Impaired nocturnal melatonin excretion and changes of immunological status in ischaemic stroke patients, Lancet 347 (1996) 692–693. A. Vergani, C. Fotino, F. D’Addio, et al., Effect of the purinergic inhibitor oxidized ATP in a model of islet allograft rejection, Diabetes 62 (2013) 1665–1675. A. Vergani, F. Gatti, K.M. Lee, et al., TIM4 regulates the anti-islet Th2 alloimmune response, Cell Transplant. (2014). R. Francese, P. Fiorina, Immunological and regenerative properties of cord blood stem cells, Clin. Immunol. 136 (2010) 309–322. F. D’Addio, A. Valderrama Vasquez, M. Ben Nasr, et al., Autologous nonmyeloablative hematopoietic stem cell transplantation in new-onset type 1 diabetes: a multicenter analysis, Diabetes 63 (2014) 3041–3046. C. Schuetz, J. Markmann, Immunogenicity of ß-cells for autologous transplantation in type 1 diabetes, Pharmacol. Res. (2015) (in press). A. Pileggi, C. Fotino, Re-engineering islet cell transplantation, Pharmacol. Res. (2015) (in press). X.C. Lin, B. El Essawy, Type 1 diabetes and regulatory cells, Pharmacol. Res. (2015) (in press). N. Komatsu, K. Okamoto, S. Sawa, et al., Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis, Nat. Med. 20 (2014) 62–68.
Moufida Ben Nasr a,b Q1 Paolo Fiorina a,b,∗ a Nephrology Division, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States Q2 b Transplant Medicine, San Raffaele Hospital, Milan, Italy ∗ Corresponding
author at: Nephrology Division, Boston Children’s Hospital, Harvard Medical School, Enders Building 5th floor, Room EN511, 300 Longwood Ave., Boston, MA 02115, United States. Tel.: +1 617 919 2624; fax: +1 617 730 0365. E-mail address: paolo.fi[email protected] (P. Fiorina) Available online xxx
Please cite this article in press as: M. Ben Nasr, P. Fiorina, Novel therapies for T1D on the horizon, Pharmacol Res (2015), http://dx.doi.org/10.1016/j.phrs.2015.03.019
157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204
205 206 207 208 209 210
211 212 213 214 215 216 217
218
