Immunotherapy for Type 1 Diabetes: Why Do Current Protocols Not Halt the Underlying Disease Process?
2016; Cell Press; Volume: 25; Issue: 2 Linguagem: Inglês
10.1016/j.cmet.2016.10.009
ISSN1932-7420
AutoresHubert Kolb, Matthias von Herrath,
Tópico(s)Pancreatic function and diabetes
ResumoT cell-directed immunosuppression only transiently delays the loss of β cell function in recent-onset type 1 diabetes. We argue here that the underlying disease process is carried by innate immune reactivity. Inducing a non-polarized functional state of local innate immunity will support regulatory T cell development and β cell proliferation. T cell-directed immunosuppression only transiently delays the loss of β cell function in recent-onset type 1 diabetes. We argue here that the underlying disease process is carried by innate immune reactivity. Inducing a non-polarized functional state of local innate immunity will support regulatory T cell development and β cell proliferation. In the late 1980s, the results of two large randomized placebo-controlled trials in patients with recent-onset type 1 diabetes (T1D) suggested that immune intervention, in this case with cyclosporin A, would halt the disease process and allow for the recovery of endogenous insulin production (Assan et al., 1985Assan R. Feutren G. Debray-Sachs M. Quiniou-Debrie M.C. Laborie C. Thomas G. Chatenoud L. Bach J.F. Metabolic and immunological effects of cyclosporin in recently diagnosed type 1 diabetes mellitus.Lancet. 1985; 1: 67-71Abstract PubMed Scopus (149) Google Scholar, The Canadian-European Randomized Control Trial Group, 1988The Canadian-European Randomized Control Trial GroupCyclosporin-induced remission of IDDM after early intervention. Association of 1 yr of cyclosporin treatment with enhanced insulin secretion.Diabetes. 1988; 37: 1574-1582Crossref PubMed Google Scholar). Unfortunately, the clinical remission observed was of limited duration (Martin et al., 1992Martin S. Pawlowski B. Greulich B. Ziegler A.G. Mandrup-Poulsen T. Mahon J. Natural course of remission in IDDM during 1st yr after diagnosis.Diabetes Care. 1992; 15: 66-74Crossref PubMed Scopus (93) Google Scholar). To date, several large controlled trials of immunomodulation and immunosuppression have been conducted, but only transient preservation of C-peptide secretion was achieved by immune intervention in some trials, with a subsequent decline of β cell function to similar levels as those seen in the control group (Ludvigsson, 2016Ludvigsson J. Therapies to preserve β-cell function in type 1 diabetes.Drugs. 2016; 76: 169-185Crossref PubMed Scopus (21) Google Scholar, Atkinson et al., 2015Atkinson M.A. von Herrath M. Powers A.C. Clare-Salzler M. Current concepts on the pathogenesis of type 1 diabetes--considerations for attempts to prevent and reverse the disease.Diabetes Care. 2015; 38: 979-988Crossref PubMed Scopus (93) Google Scholar, von Herrath et al., 2013von Herrath M. Peakman M. Roep B. Progress in immune-based therapies for type 1 diabetes.Clin. Exp. Immunol. 2013; 172: 186-202Crossref PubMed Scopus (54) Google Scholar). In this Essay, we will discuss the immune versus autoimmune nature of T1D, take into consideration data from the non-obese diabetic (NOD) mouse model of T1D, and discuss results from immunotherapy trials in two other cell-mediated "autoimmune" diseases, multiple sclerosis and rheumatoid arthritis (RA). The synthesis of these data provides a novel perspective for molecular targets of immune intervention and potential strategies for tailoring the therapeutic protocol to individual patient responses in T1D. We will not discuss other approaches to treat or cure T1D, such as transplantation of insulin-producing tissue or stem cells, applying closed loop systems for insulin delivery or gene surgery. Most attempts to reverse T1D or to prevent the loss of residual β cell function have been conducted in patients early (up to 3 months) after diabetes diagnosis, as were carried out previously in the trials of cyclosporin A. Some approaches have targeted β cells for protection and/or regeneration, but most trials have attempted to restore immune tolerance by pharmacological immunomodulation or autoantigen vaccination. Combinations of potentially complementary treatment modalities have also been used (von Herrath et al., 2013von Herrath M. Peakman M. Roep B. Progress in immune-based therapies for type 1 diabetes.Clin. Exp. Immunol. 2013; 172: 186-202Crossref PubMed Scopus (54) Google Scholar, Atkinson et al., 2015Atkinson M.A. von Herrath M. Powers A.C. Clare-Salzler M. Current concepts on the pathogenesis of type 1 diabetes--considerations for attempts to prevent and reverse the disease.Diabetes Care. 2015; 38: 979-988Crossref PubMed Scopus (93) Google Scholar, Ludvigsson, 2016Ludvigsson J. Therapies to preserve β-cell function in type 1 diabetes.Drugs. 2016; 76: 169-185Crossref PubMed Scopus (21) Google Scholar). Most trials enrolled fewer than 20–30 patients per group, and, despite these small numbers, some of the studies reported a significant difference in stimulated C-peptide secretion between groups. Results from studies attempting to replicate positive outcomes in large phase II or phase III trials have reported significant delay in the loss of β cell function at 1 or 2 years but a subsequent further decline in the case of treatment with CTLA4-Ig (Orban et al., 2014Orban T. Bundy B. Becker D.J. Dimeglio L.A. Gitelman S.E. Goland R. Gottlieb P.A. Greenbaum C.J. Marks J.B. Monzavi R. et al.Type 1 Diabetes TrialNet Abatacept Study GroupCostimulation modulation with abatacept in patients with recent-onset type 1 diabetes: follow-up 1 year after cessation of treatment.Diabetes Care. 2014; 37: 1069-1075Crossref PubMed Scopus (121) Google Scholar), anti-CD20 (Pescovitz et al., 2014Pescovitz M.D. Greenbaum C.J. Bundy B. Becker D.J. Gitelman S.E. Goland R. Gottlieb P.A. Marks J.B. Moran A. Raskin P. et al.Type 1 Diabetes TrialNet Anti-CD20 Study GroupB-lymphocyte depletion with rituximab and β-cell function: two-year results.Diabetes Care. 2014; 37: 453-459Crossref PubMed Scopus (151) Google Scholar), or CD3 antibody otelixizumab (Keymeulen et al., 2010Keymeulen B. Walter M. Mathieu C. Kaufman L. Gorus F. Hilbrands R. Vandemeulebroucke E. Van de Velde U. Crenier L. De Block C. et al.Four-year metabolic outcome of a randomised controlled CD3-antibody trial in recent-onset type 1 diabetic patients depends on their age and baseline residual beta cell mass.Diabetologia. 2010; 53: 614-623Crossref PubMed Scopus (254) Google Scholar). There was no significant difference for the primary endpoint in trials of interleukin-1 antagonism (Moran et al., 2013Moran A. Bundy B. Becker D.J. DiMeglio L.A. Gitelman S.E. Goland R. Greenbaum C.J. Herold K.C. Marks J.B. Raskin P. et al.Type 1 Diabetes TrialNet Canakinumab Study GroupAIDA Study GroupInterleukin-1 antagonism in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials.Lancet. 2013; 381: 1905-1915Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar), anti-thymocyte globulin (Gitelman et al., 2013Gitelman S.E. Gottlieb P.A. Rigby M.R. Felner E.I. Willi S.M. Fisher L.K. Moran A. Gottschalk M. Moore W.V. Pinckney A. et al.START Study TeamAntithymocyte globulin treatment for patients with recent-onset type 1 diabetes: 12-month results of a randomised, placebo-controlled, phase 2 trial.Lancet Diabetes Endocrinol. 2013; 1: 306-316Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar), glutamate decarboxylase vaccination (Ludvigsson et al., 2012Ludvigsson J. Krisky D. Casas R. Battelino T. Castaño L. Greening J. Kordonouri O. Otonkoski T. Pozzilli P. Robert J.J. et al.GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus.N. Engl. J. Med. 2012; 366: 433-442Crossref PubMed Scopus (246) Google Scholar, Wherrett et al., 2011Wherrett D.K. Bundy B. Becker D.J. DiMeglio L.A. Gitelman S.E. Goland R. Gottlieb P.A. Greenbaum C.J. Herold K.C. Marks J.B. et al.Type 1 Diabetes TrialNet GAD Study GroupAntigen-based therapy with glutamic acid decarboxylase (GAD) vaccine in patients with recent-onset type 1 diabetes: a randomised double-blind trial.Lancet. 2011; 378: 319-327Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar), LFA-3/IgG1 fusion protein (Rigby et al., 2013Rigby M.R. DiMeglio L.A. Rendell M.S. Felner E.I. Dostou J.M. Gitelman S.E. Patel C.M. Griffin K.J. Tsalikian E. Gottlieb P.A. et al.T1DAL Study TeamTargeting of memory T cells with alefacept in new-onset type 1 diabetes (T1DAL study): 12 month results of a randomised, double-blind, placebo-controlled phase 2 trial.Lancet Diabetes Endocrinol. 2013; 1: 284-294Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar), BCG vaccination (Allen et al., 1999Allen H.F. Klingensmith G.J. Jensen P. Simoes E. Hayward A. Chase H.P. Effect of Bacillus Calmette-Guerin vaccination on new-onset type 1 diabetes. A randomized clinical study.Diabetes Care. 1999; 22: 1703-1707Crossref PubMed Scopus (99) Google Scholar), CD3 antibody teplizumab (Sherry et al., 2011Sherry N. Hagopian W. Ludvigsson J. Jain S.M. Wahlen J. Ferry Jr., R.J. Bode B. Aronoff S. Holland C. Carlin D. et al.Protégé Trial InvestigatorsTeplizumab for treatment of type 1 diabetes (Protégé study): 1-year results from a randomised, placebo-controlled trial.Lancet. 2011; 378: 487-497Abstract Full Text Full Text PDF PubMed Scopus (346) Google Scholar), or otelixizumab (DEFEND-2 trial) (Ambery et al., 2014Ambery P. Donner T.W. Biswas N. Donaldson J. Parkin J. Dayan C.M. Efficacy and safety of low-dose otelixizumab anti-CD3 monoclonal antibody in preserving C-peptide secretion in adolescent type 1 diabetes: DEFEND-2, a randomized, placebo-controlled, double-blind, multi-centre study.Diabet. Med. 2014; 31: 399-402Crossref PubMed Scopus (46) Google Scholar). These negative results, at least in the long term, are in striking contrast to those seen with allotransplantation of pancreatic tissue to patients with T1D. In these studies, after 3 years, sufficient insulin production was seen in more than 80% of grafts with rapamycin-based maintenance therapy (Gruessner and Gruessner, 2013Gruessner R.W. Gruessner A.C. Pancreas transplant alone: a procedure coming of age.Diabetes Care. 2013; 36: 2440-2447Crossref PubMed Scopus (56) Google Scholar). Graft survival was lower with previous cyclosporin A-based therapies, around 40%–60% after 1 year, but still well above the outcome of cyclosporin A trials conducted at the same time in recent onset T1D (Assan et al., 1985Assan R. Feutren G. Debray-Sachs M. Quiniou-Debrie M.C. Laborie C. Thomas G. Chatenoud L. Bach J.F. Metabolic and immunological effects of cyclosporin in recently diagnosed type 1 diabetes mellitus.Lancet. 1985; 1: 67-71Abstract PubMed Scopus (149) Google Scholar, The Canadian-European Randomized Control Trial Group, 1988The Canadian-European Randomized Control Trial GroupCyclosporin-induced remission of IDDM after early intervention. Association of 1 yr of cyclosporin treatment with enhanced insulin secretion.Diabetes. 1988; 37: 1574-1582Crossref PubMed Google Scholar). We conclude that conventional T cell-directed immunosuppression is effective in preventing rejection of pancreas allotransplants. Recipients of pancreas grafts have usually had T1D for many years and have received a kidney transplant prior to, or together with, the pancreas graft. In some graft recipients, humoral islet autoimmunity reappeared despite the long duration of disease. Recurrence of diabetes occurred in less than 10% of graft recipients. Insulitis was observed in these cases, where biopsies were performed. Interestingly, additional immunosuppression failed to halt the progression of islet autoimmunity and diabetes recurrence (Burke et al., 2015Burke 3rd, G.W. Vendrame F. Virdi S.K. Ciancio G. Chen L. Ruiz P. Messinger S. Reijonen H.K. Pugliese A. Lessons from pancreas transplantation in type 1 diabetes: recurrence of islet autoimmunity.Curr. Diab. Rep. 2015; 15: 121Crossref PubMed Scopus (42) Google Scholar, Vendrame et al., 2016Vendrame F. Hopfner Y.Y. Diamantopoulos S. Virdi S.K. Allende G. Snowhite I.V. Reijonen H.K. Chen L. Ruiz P. Ciancio G. et al.Risk factors for type 1 diabetes recurrence in immunosuppressed recipients of simultaneous pancreas-kidney transplants.Am. J. Transplant. 2016; 16: 235-245Crossref PubMed Scopus (37) Google Scholar). This finding suggests that islet autoimmunity may reappear in some allograft recipients despite the absence of human leukocyte antigen (HLA) identity and that this process is different from T cell-mediated allograft rejection. Textbook and journal papers usually describe T1D as an autoimmune disease. However, formal proof of such a mechanism is lacking. The available data suggest that β cell destruction results from immune activity but not necessarily autoimmune activity (Figure 1). One piece of data supporting an immune cause for T1D comes from the observation that T1D occurred in a myeloablated nondiabetic recipient several years after receiving a bone marrow graft from her HLA-identical brother who had insulin-dependent diabetes (Lampeter et al., 1993Lampeter E.F. Homberg M. Quabeck K. Schaefer U.W. Wernet P. Bertrams J. Grosse-Wilde H. Gries F.A. Kolb H. Transfer of insulin-dependent diabetes between HLA-identical siblings by bone marrow transplantation.Lancet. 1993; 341: 1243-1244Abstract PubMed Scopus (187) Google Scholar). Islet-cell antibody positivity also developed several years after bone marrow transfer. A search of the International Bone Marrow Transplantation Registry uncovered further similar cases of diabetes transfer if there was similarity for HLA types and follow-up for several years (Lampeter et al., 1998Lampeter E.F. McCann S.R. Kolb H. Transfer of diabetes type 1 by bone-marrow transplantation.Lancet. 1998; 351: 568-569Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar). Unfortunately, it is not possible to exclude the involvement of a non-autoimmune mechanism, such as the cotransfer of viruses or the induction of dormant viruses and subsequent immune response against the recipients' β cells by islet antigen-specific T cells in the bone marrow transplant. Furthermore, it is possible that leukocytes, other than T cells in the graft, carried the disease predisposition. A major pathogenic role of islet autoantibodies seems improbable since T1D has been known to occur despite severe hereditary B cell deficiency (Martin et al., 2001Martin S. Wolf-Eichbaum D. Duinkerken G. Scherbaum W.A. Kolb H. Noordzij J.G. Roep B.O. Development of type 1 diabetes despite severe hereditary B-lymphocyte deficiency.N. Engl. J. Med. 2001; 345: 1036-1040Crossref PubMed Scopus (226) Google Scholar); however, B cells probably do play a role in antigen presentation and immunoregulation during this process (Hinman et al., 2014Hinman R.M. Smith M.J. Cambier J.C. B cells and type 1 diabetes …in mice and men.Immunol. Lett. 2014; 160: 128-132Crossref PubMed Scopus (23) Google Scholar). Additional observations suggest a causative role of immune reactivity in β cell destruction but do not prove its autoimmune nature. In a study of 119 pancreases obtained postmortem from patients with T1D, insulitis was almost only seen in islets with insulin-positive cells (Foulis et al., 1986Foulis A.K. Liddle C.N. Farquharson M.A. Richmond J.A. Weir R.S. The histopathology of the pancreas in type 1 (insulin-dependent) diabetes mellitus: a 25-year review of deaths in patients under 20 years of age in the United Kingdom.Diabetologia. 1986; 29: 267-274Crossref PubMed Scopus (395) Google Scholar), indicating that the immune infiltrate was β cell directed. This important finding was confirmed recently by Campbell-Thompson et al., 2016Campbell-Thompson M. Fu A. Kaddis J.S. Wasserfall C. Schatz D.A. Pugliese A. Atkinson M.A. Insulitis and β-cell mass in the natural history of type 1 diabetes.Diabetes. 2016; 65: 719-731Crossref PubMed Scopus (230) Google Scholar. It is possible that viral infections may affect only the β cells (de Beeck and Eizirik, 2016de Beeck A.O. Eizirik D.L. Viral infections in type 1 diabetes mellitus—why the β cells?.Nat. Rev. Endocrinol. 2016; 12: 263-273Crossref PubMed Scopus (164) Google Scholar) and may therefore cause lymphocyte infiltration and account for their immune destruction. β cell autoimmunity would be an epiphenomenon in this case. Another piece of evidence to suggest a causative role of immune reactivity in T1D development is that transplantation of pancreas tissue between identical siblings led to a reappearance of the disease in the former T1D recipient within 3 months, leading to massive lymphocytic insulitis and selective β cell loss. Immunosuppressive treatment prevented disease recurrence (Sutherland et al., 1989Sutherland D.E. Moudry K.C. Fryd D.S. Results of pancreas-transplant registry.Diabetes. 1989; 38: 46-54Crossref PubMed Google Scholar). The mechanism of such rapid deterioration of insulin production may be different to the slow loss of β cell function during the natural course of T1D or from the slow recurrence of diabetes among those recipients of pancreas allografts who subsequently became islet autoantibody positive. In both latter cases, conventional immunosuppression failed to preserve β cell function, as described above. A third argument in favor of a causative role of immune reactivity is the role of the HLA immune gene complex as a major genetic determinant (Noble, 2015Noble J.A. Immunogenetics of type 1 diabetes: a comprehensive review.J. Autoimmun. 2015; 64: 101-112Crossref PubMed Scopus (128) Google Scholar). Major histocompatibility complex (MHC) class II genes and others in the MHC region are critical for T cell activation but may also impact inflammation. Finally, immunosuppressive therapy did have some protective effect, albeit transient, on β cell function in recent-onset T1D (Assan et al., 1985Assan R. Feutren G. Debray-Sachs M. Quiniou-Debrie M.C. Laborie C. Thomas G. Chatenoud L. Bach J.F. Metabolic and immunological effects of cyclosporin in recently diagnosed type 1 diabetes mellitus.Lancet. 1985; 1: 67-71Abstract PubMed Scopus (149) Google Scholar, The Canadian-European Randomized Control Trial Group, 1988The Canadian-European Randomized Control Trial GroupCyclosporin-induced remission of IDDM after early intervention. Association of 1 yr of cyclosporin treatment with enhanced insulin secretion.Diabetes. 1988; 37: 1574-1582Crossref PubMed Google Scholar). None of the arguments listed confirms the autoimmune nature of islet inflammation, which may be due to viral activity, the expression of neo-antigens, or danger signals on β cells. One such example is immune-mediated tissue damage during persistent Helicobacter pylori infection of the stomach (Smith et al., 2016Smith S.M. Freeley M. Moynagh P.N. Kelleher D.P. Differential modulation of Helicobacter pylori lipopolysaccharide-mediated TLR2 signaling by individual Pellino proteins.Helicobacter. 2016; (Published online June 15, 2016)PubMed Google Scholar); another example is small intestinal tissue damage during innate and adaptive immune reactivity toward gluten and associated proteins (Lebwohl et al., 2015Lebwohl B. Ludvigsson J.F. Green P.H. Celiac disease and non-celiac gluten sensitivity.BMJ. 2015; 351: h4347Crossref PubMed Scopus (204) Google Scholar, Nikulina et al., 2004Nikulina M. Habich C. Flohé S.B. Scott F.W. Kolb H. Wheat gluten causes dendritic cell maturation and chemokine secretion.J. Immunol. 2004; 173: 1925-1933Crossref PubMed Scopus (83) Google Scholar). Whatever the cause of islet inflammation in T1D, β cell loss appears to be dependent on immune reactivity and hence can be considered as immune mediated and susceptible to immunotherapy. A simple explanation regarding the lack of long-term success with immunotherapy could be that intervention at the time of overt T1D comes too late to rescue β cell function. However, there is evidence for substantial C-peptide secretion in many patients at diagnosis and partial, but transient, recovery thereafter (DiMeglio et al., 2016DiMeglio L.A. Cheng P. Beck R.W. Kollman C. Ruedy K.J. Slover R. Aye T. Weinzimer S.A. Bremer A.A. Buckingham B. Diabetes Research in Children Network (DirecNet); Type 1 Diabetes TrialNet Study GroupChanges in beta cell function during the proximate post-diagnosis period in persons with type 1 diabetes.Pediatr. Diabetes. 2016; 17: 237-243Crossref PubMed Scopus (8) Google Scholar, Chmelova et al., 2015Chmelova H. Cohrs C.M. Chouinard J.A. Petzold C. Kuhn M. Chen C. Roeder I. Kretschmer K. Speier S. Distinct roles of β-cell mass and function during type 1 diabetes onset and remission.Diabetes. 2015; 64: 2148-2160Crossref PubMed Scopus (39) Google Scholar). β cell function is already affected in the period prior to the onset of overt diabetes, as evident from impaired insulin production in response to intravenous infusion of glucose (Insel et al., 2015Insel R.A. Dunne J.L. Atkinson M.A. Chiang J.L. Dabelea D. Gottlieb P.A. Greenbaum C.J. Herold K.C. Krischer J.P. Lernmark Å. et al.Staging presymptomatic type 1 diabetes: a scientific statement of JDRF, the Endocrine Society, and the American Diabetes Association.Diabetes Care. 2015; 38: 1964-1974Crossref PubMed Scopus (482) Google Scholar, Vendrame et al., 2016Vendrame F. Hopfner Y.Y. Diamantopoulos S. Virdi S.K. Allende G. Snowhite I.V. Reijonen H.K. Chen L. Ruiz P. Ciancio G. et al.Risk factors for type 1 diabetes recurrence in immunosuppressed recipients of simultaneous pancreas-kidney transplants.Am. J. Transplant. 2016; 16: 235-245Crossref PubMed Scopus (37) Google Scholar). The partial recovery after the onset of insulin treatment appears to be due to reduced stress because of metabolic normalization. Indeed, islets isolated from patients with T1D are deficient in glucose-induced insulin secretion and show recovery of the insulin response to glucose if kept under euglycemic conditions for a few days (Krogvold et al., 2015Krogvold L. Skog O. Sundström G. Edwin B. Buanes T. Hanssen K.F. Ludvigsson J. Grabherr M. Korsgren O. Dahl-Jørgensen K. Function of Isolated Pancreatic Islets From Patients at Onset of Type 1 Diabetes: Insulin Secretion Can Be Restored After Some Days in a Nondiabetogenic Environment In Vitro: Results From the DiViD Study.Diabetes. 2015; 64: 2506-2512Crossref PubMed Scopus (65) Google Scholar). We therefore conclude that substantial recovery of residual β cell function could be reached in the context of normalized glycemia and inhibition of the β cell destructive process in the pancreas after treatment with immune therapy in patients with recent-onset T1D. Whether the residual β cell mass at diabetes diagnosis suffices to provide long-term remission is not known. In normal islets, there is functional heterogeneity between β cells. Depending on the ambient glucose concentration, only 5%–40% of cells may respond with insulin production (Pipeleers, 1992Pipeleers D.G. Heterogeneity in pancreatic beta-cell population.Diabetes. 1992; 41: 777-781Crossref PubMed Scopus (169) Google Scholar). At diabetes onset, because of the decreased number of insulin-positive cells, a much higher percentage of β cells will need to be continuously active, with the risk of chronic metabolic stress. Indeed, β cell function may deteriorate months or years after partial pancreatectomy (Jalleh and Williamson, 1992Jalleh R.P. Williamson R.C. Pancreatic exocrine and endocrine function after operations for chronic pancreatitis.Ann. Surg. 1992; 216: 656-662Crossref PubMed Scopus (114) Google Scholar) but usually the opposite happens, i.e., there is initial deterioration of endocrine function immediately after partial pancreatectomy and then recovery to pre-surgery levels in the following years (Menge et al., 2012Menge B.A. Breuer T.G. Ritter P.R. Uhl W. Schmidt W.E. Meier J.J. Long-term recovery of β-cell function after partial pancreatectomy in humans.Metabolism. 2012; 61: 620-624Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar). We can also glean information from the clinical setting of segmental pancreas transplantation (around 50% of tissue) from nondiabetic living donors to recipients with T1D. Again, long-term survival of the reduced β cell mass is observed in graft recipients (Robertson, 2004Robertson R.P. Consequences on beta-cell function and reserve after long-term pancreas transplantation.Diabetes. 2004; 53: 633-644Crossref PubMed Scopus (61) Google Scholar). Among pancreas segment donors, diabetes is a rare outcome, but it does occur (Gruessner et al., 2011Gruessner R.W. Pugliese A. Reijonen H.K. Gruessner S. Jie T. Desai C. Sutherland D.E. Burke 3rd, G.W. Development of diabetes mellitus in living pancreas donors and recipients.Expert Rev. Clin. Immunol. 2011; 7: 543-551Crossref PubMed Scopus (7) Google Scholar). The limited β cell mass at diabetes onset should show substantial recovery of function if the disease process is stopped by an appropriate immune therapy, but there may still be deterioration of β cell function in the long term, mainly because of metabolic stress. NOD mice are considered a useful model of human T1D because disease development is immune mediated, targets β cells and similar autoantigens as in man, and shares as major diabetes risk gene(s) the MHC complex (Pearson et al., 2016Pearson J.A. Wong F.S. Wen L. The importance of the Non Obese Diabetic (NOD) mouse model in autoimmune diabetes.J. Autoimmun. 2016; 66: 76-88Crossref PubMed Scopus (165) Google Scholar). The major difference is in the time course of disease. While most cases of diabetes are diagnosed between 3 and 6 months of age in mice, the same endpoint in man is usually reached after many years or even decades of life. This fits with massive mononuclear infiltration of most mouse islets, in particular at the periphery, whereas there is only sparse intra-islet infiltration in approximately 10% of islets in human T1D, even in individuals positive for multiple autoantibodies or in pancreatic biopsies taken right after diagnosis of T1D (In't Veld, 2014In't Veld P. Insulitis in human type 1 diabetes: a comparison between patients and animal models.Semin. Immunopathol. 2014; 36: 569-579Crossref PubMed Scopus (85) Google Scholar) (Figure 2). Another difference is the preferential development of overt diabetes in female mice whereas in humans there is a moderately higher rate seen in males (Bao et al., 2002Bao M. Yang Y. Jun H.S. Yoon J.W. Molecular mechanisms for gender differences in susceptibility to T cell-mediated autoimmune diabetes in nonobese diabetic mice.J. Immunol. 2002; 168: 5369-5375Crossref PubMed Scopus (96) Google Scholar, Stanescu et al., 2012Stanescu D.E. Lord K. Lipman T.H. The epidemiology of type 1 diabetes in children.Endocrinol. Metab. Clin. North Am. 2012; 41: 679-694Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar, Diaz-Valencia et al., 2015Diaz-Valencia P.A. Bougnères P. Valleron A.J. Global epidemiology of type 1 diabetes in young adults and adults: a systematic review.BMC Public Health. 2015; 15: 255Crossref PubMed Scopus (157) Google Scholar). Both, female and male NOD mice develop islet autoimmunity and insulitis, but there appears to be a stronger Th1 bias of immune reactivity in female mice (Bao et al., 2002Bao M. Yang Y. Jun H.S. Yoon J.W. Molecular mechanisms for gender differences in susceptibility to T cell-mediated autoimmune diabetes in nonobese diabetic mice.J. Immunol. 2002; 168: 5369-5375Crossref PubMed Scopus (96) Google Scholar). Clearly, the disease process is much faster in mice, with fulminant immune activation and associated lymphocytic proliferation. Since immunosuppressive therapies preferentially target cells during the amplification steps of immune reactivity, it is conceivable that clinical effects of such therapies are stronger in mice than in the slowly progressing immune process in man. The latter probably requires much more restimulation of T cell reactivity by antigen-presenting cells or other contributions of innate immune cells than the islet-destructive immune reaction, which lasts only weeks or a few months in NOD mice. One possible reason for the slower disease process in man can be found at the level of the β cell. Human cells are equipped with much stronger defense and repair systems than rodent cells, in accordance with their longer lifespan. Human islet cells exhibit a greater resistance to toxins than mouse islets, and this appears to be due to increased expression of heat shock proteins and anti-oxidant enzymes (Welsh et al., 1995Welsh N. Margulis B. Borg L.A. Wiklund H.J. Saldeen J. Flodström M. Mello M.A. Andersson A. Pipeleers D.G. Hellerström C. et al.Differences in the expression of heat-shock proteins and antioxidant enzymes between human and rodent pancreatic islets: implications for the pathogenesis of insulin-dependent diabetes mellitus.Mol. Med. 1995; 1: 806-820Crossref PubMed Google Scholar). Fewer cell deaths means fewer islet autoantigens (or viral antigens) released for enhancement of local immune reactivity in man. Conversely, rapid β cell death in NOD mice is expected to provide ample autoantigens, allowing for fulminant immune reactivity and concomitant susceptibility to antiproliferative immune therapy. Furthermore, the human immune system exhibits more complex regulation than the mouse counterpart, which will lead to less detrimental excessive immune reactivity to foreign or self-determinants. For example, the pro-inflammatory activation of cyclooxygenase 2 by nuclear factor kappa B is more tightly regulated in man than in rodents (Nguyen et al., 2015Nguyen L.K. Cavadas M.A. Kholodenko B.N. Frank T.D. Cheong A. Species differential regulation of COX2 can be described by an NFκB-dependent logic AND gate.Cell. Mol. Life Sci. 2015; 72: 2431-2443Crossref PubMed Scopus (17) Google Scholar). These differences, at the level of the β cell and of immune regulation, are expected to render immunotherapy approaches more difficult in human patients than in NOD mice. Multiple sclerosis and rheumatoid arthritis share with T1D a p
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