Type 1 Diabetes — Does Suppressing T Cells Increase Insulin?
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《新英格兰医药杂志》
During the ominous prelude to the onset of type 1 diabetes, the pancreatic-islet beta cells become the targets of a specific autoimmune attack, which ultimately results in diabetes. Although major advances have led to an improved understanding of this disease, important gaps in knowledge must be bridged before insulin replacement is shelved forever. The report by Keymeulen et al.1 in this issue of the Journal is further testimony to how complicated it will be to find a treatment that is superior to insulin alone.
The development of type 1 diabetes may be viewed as a two-step process. In the first step, presumed environmental triggers cause the destruction of beta cells. It is assumed that pancreatic antigen-presenting cells engulf dead beta cells. The antigen-presenting cells are thought to migrate to lymph nodes that drain the pancreas and in which islet-beta-cell–specific antigen presentation takes place.2 CD4+ T lymphocytes with T-cell receptors that recognize beta-cell peptides lodged in a groove in the HLA class II molecule may then be activated, which initiates an islet autoimmune reaction.
Islet autoimmunity is best detected with the use of standardized tests for autoantibodies to insulin, IA-2, or glutamic acid decarboxylase (GAD65).3,4 Autoantibodies can be present in some patients for more than a decade before the onset of diabetes, and it is well documented that these islet autoantibodies, in combination, predict type 1 diabetes.5
After autoantibodies have developed, there is a second step, in which genetic as well as environmental factors may aggravate the islet autoimmunity. Perhaps CD8+ cytotoxic T cells are induced, leading to a rapid onslaught on beta cells. Depending on the insulin sensitivity and the age of the patient, hyperglycemia ensues when 80 to 90 percent of beta cells have been destroyed. The older the patient, the more residual beta cells appear to remain at the onset of hyperglycemia. Sadly, the disease process is more aggressive in young children, and type 1 diabetes is being diagnosed at progressively younger ages, even though the total incidence may not be increasing.6
The age-dependent clinical onset of type 1 diabetes is also critical in an evaluation of the study by Keymeulen et al. The particular ChAglyCD3 antibody the investigators used is engineered on aglycosylated human IgG1. Only insulin-requiring patients between the ages of 12 and 39 years who had islet-cell antibodies, GAD65 autoantibodies, or both, as well as C-peptide levels greater than 0.20 nmol per liter, were included. The entry criteria ensured that patients with type 1 diabetes who already had had a sizable loss of beta cells at the time of diagnosis did not participate — a factor that was important for reasons discussed below.
Why was an antibody against CD3+ T cells used in a phase 2 clinical trial? Immunosuppressive or immunomodulating agents have been used in an increasing number of clinical studies, since the evidence has been growing that type 1 diabetes is an autoimmune disease. Numerous trials that were either open or poorly controlled were attempted, and in studies during the past 30 years, patients with type 1 diabetes have been exposed to a host of immunosuppressive or immunomodulating agents.7 Cyclosporine was the first immunosuppressive agent that was used in important placebo-controlled, double-blind clinical trials.8,9 Beta-cell function was preserved by such an approach, although rarely beyond 12 months. Furthermore, calcineurin nephrotoxicity precluded additional clinical studies.10
The ability to predict type 1 diabetes by detecting the presence of islet-cell autoantibodies3,5 — and the results of studies in laboratory rats and mice with spontaneous diabetes — led to clinical trials of methods to prevent or delay the clinical onset of the disease.11,12 The administration of parenteral insulin was effective in the prevention of diabetes in the BioBreeding (BB) rat and the nonobese diabetic (NOD) mouse, but the strategy did not prevent the onset of the disease in first-degree relatives of patients with type 1 diabetes who had tested positive for the islet-cell autoantibody.11 Likewise, although nicotinamide prevented diabetes in the NOD mouse, it was ineffective in a controlled trial in humans.12
The study by Keymeulen et al. was based on both experimental animal models and clinical data suggesting that CD3 monoclonal antibodies might affect autoimmune diabetes. Preclinical studies with CD3 monoclonal antibodies were highly effective in the NOD mouse. The study by Keymeulen et al. was also preceded by a placebo-controlled trial in 24 patients with new-onset type 1 diabetes in which another type of humanized CD3 monoclonal antibody was used.13 The treatment effect on insulin responsiveness lasted for at least 12 months after diagnosis.13 The mechanisms of action remain unclear, but it is speculated that induction of CD8+ T cells and perhaps so-called regulatory CD4+CD25+ T cells might be of importance.
Two aspects of the present study are particularly important and will have implications for future attempts to treat type 1 diabetes with CD3 monoclonal antibodies or similar agents. The first is safety. Is it an acceptable risk that the ChAglyCD3 antibody was associated with an influenzalike syndrome and symptoms of Epstein–Barr viral mononucleosis? The long-term effects of this treatment and the question of whether the induction of virus-antigen–specific CD8+ T cells was important to the improved beta-cell function must be determined.
Another important aspect of the study by Keymeulen et al. is the finding that the ChAglyCD3 antibody was effective only in a subgroup of patients — those among the 80 patients who initially had increased residual beta-cell function (at or above the 50th percentile). Studies that have analyzed the age of patients at the onset of type 1 diabetes, the residual beta-cell function, the distribution of HLA genotypes, and autoantibody positivity suggest that the older the patient, the more C peptide is produced at the time of clinical diagnosis and the fewer high-risk HLA genotypes are present.14 None of these factors appeared to be important in the outcome of the present study, but it is likely that many more teenagers with new-onset diabetes will need to be studied. An additional group that merits further investigation is patients with type 2 diabetes and GAD65 autoantibody, identified as so-called latent autoimmune diabetes in adults.4
The fact the ChAglyCD3 antibody appears effective only when substantial function of residual beta cells is present may limit its applicability. On the other hand, the effect of the ChAglyCD3 antibody may signify that a T-cell–dependent destructive process has to be active before a treatment effect is achieved. If the beta-cell killing has gone too far, there is no point in injecting the CD3 monoclonal antibody. Provided that the treatment is safe, it may be reasonable to consider therapy with CD3 monoclonal antibody for patients with a genetic risk of type 1 diabetes who test positive for islet autoantibody. Screening to detect such patients is carried out by the TrialNet network (www.diabetestrialnet.org/hindex.html), sponsored by the National Institutes of Health, and studied in detail in the TEDDY trial (The Environmental Determinants of Diabetes in the Young; www.teddystudy.org).
The demonstration that the ChAglyCD3 antibody was effective primarily in patients with substantial residual beta-cell function suggests that it may be necessary to increase the efficacy of immunotherapy for type 1 diabetes. A recent phase 2 study suggests that the treatment of latent autoimmune diabetes in adults with alum-formulated GAD65 is safe and may also have a beneficial effect on fasting C-peptide levels.15 If CD3 monoclonal antibodies are shown to be safe, perhaps their use in combination with agents for inducing immune tolerance could lead to improved therapies for type 1 diabetes.
Source Information
From the Department of Medicine, University of Washington, Seattle.
References
Keymeulen B, Vandemeulebroucke E, Ziegler AG, et al. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med 2005;352:2598-2608.
Kent SC, Chen Y, Bregoli L, et al. Expanded T cells from pancreatic lymph nodes of type 1 diabetic subjects recognize an insulin epitope. Nature 2005;435:224-228.
Krischer JP, Cuthbertson DD, Yu L, et al. Screening strategies for the identification of multiple antibody-positive relatives of individuals with type 1 diabetes. J Clin Endocrinol Metab 2003;88:103-108.
Falorni A, Brozzetti A. Diabetes-related antibodies in adult diabetic patients. Best Pract Res Clin Endocrinol Metab 2005;19:119-133.
Notkins AL, Lernmark ?. Autoimmune type 1 diabetes: resolved and unresolved issues. J Clin Invest 2001;108:1247-1252.
Pundziute-Lycka A, Dahlquist G, Nystrom L, et al. The incidence of type I diabetes has not increase but shifted to a younger age at diagnosis in the 0-34 years group in Sweden 1983-1998. Diabetologia 2002;45:783-791.
Skyler JS, Marks JB. Immune intervention in type 1 diabetes mellitus. Diabetes Rev 1993;1:15-42.
The Canadian-European Randomized Control Trial Group. Cyclosporin-induced remission of IDDM after early intervention: association of 1 yr of cyclosporin treatment with enhanced insulin secretion. Diabetes 1988;37:1574-1582.
Bougneres PF, Carel JC, Castano L, et al. Factors associated with early remission of type 1 diabetes in children treated with cyclosporine. N Engl J Med 1988;318:663-670.
Parving HH, Tarnow L, Nielsen FS, et al. Cyclosporine nephrotoxicity in type 1 diabetic patients: a 7-year follow-up study. Diabetes Care 1999;22:478-483.
Diabetes Prevention Trial-Type 1 Diabetes Study Group. Effects of insulin in relatives of patients with type 1 diabetes mellitus. N Engl J Med 2002;346:1685-1691.
Gale EA, Bingley PJ, Emmett CL, Collier T. European Nicotinamide Diabetes Intervention Trial (ENDIT): a randomised controlled trial of intervention before the onset of type 1 diabetes. Lancet 2004;363:925-931.
Herold KC, Hagopian W, Auger JA, et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med 2002;346:1692-1698.
Graham J, Hagopian WA, Kockum I, et al. Genetic effects on age-dependent onset and islet cell autoantibody markers in type 1 diabetes. Diabetes 2002;51:1346-1355.(?ke Lernmark, Med.Dr.)
The development of type 1 diabetes may be viewed as a two-step process. In the first step, presumed environmental triggers cause the destruction of beta cells. It is assumed that pancreatic antigen-presenting cells engulf dead beta cells. The antigen-presenting cells are thought to migrate to lymph nodes that drain the pancreas and in which islet-beta-cell–specific antigen presentation takes place.2 CD4+ T lymphocytes with T-cell receptors that recognize beta-cell peptides lodged in a groove in the HLA class II molecule may then be activated, which initiates an islet autoimmune reaction.
Islet autoimmunity is best detected with the use of standardized tests for autoantibodies to insulin, IA-2, or glutamic acid decarboxylase (GAD65).3,4 Autoantibodies can be present in some patients for more than a decade before the onset of diabetes, and it is well documented that these islet autoantibodies, in combination, predict type 1 diabetes.5
After autoantibodies have developed, there is a second step, in which genetic as well as environmental factors may aggravate the islet autoimmunity. Perhaps CD8+ cytotoxic T cells are induced, leading to a rapid onslaught on beta cells. Depending on the insulin sensitivity and the age of the patient, hyperglycemia ensues when 80 to 90 percent of beta cells have been destroyed. The older the patient, the more residual beta cells appear to remain at the onset of hyperglycemia. Sadly, the disease process is more aggressive in young children, and type 1 diabetes is being diagnosed at progressively younger ages, even though the total incidence may not be increasing.6
The age-dependent clinical onset of type 1 diabetes is also critical in an evaluation of the study by Keymeulen et al. The particular ChAglyCD3 antibody the investigators used is engineered on aglycosylated human IgG1. Only insulin-requiring patients between the ages of 12 and 39 years who had islet-cell antibodies, GAD65 autoantibodies, or both, as well as C-peptide levels greater than 0.20 nmol per liter, were included. The entry criteria ensured that patients with type 1 diabetes who already had had a sizable loss of beta cells at the time of diagnosis did not participate — a factor that was important for reasons discussed below.
Why was an antibody against CD3+ T cells used in a phase 2 clinical trial? Immunosuppressive or immunomodulating agents have been used in an increasing number of clinical studies, since the evidence has been growing that type 1 diabetes is an autoimmune disease. Numerous trials that were either open or poorly controlled were attempted, and in studies during the past 30 years, patients with type 1 diabetes have been exposed to a host of immunosuppressive or immunomodulating agents.7 Cyclosporine was the first immunosuppressive agent that was used in important placebo-controlled, double-blind clinical trials.8,9 Beta-cell function was preserved by such an approach, although rarely beyond 12 months. Furthermore, calcineurin nephrotoxicity precluded additional clinical studies.10
The ability to predict type 1 diabetes by detecting the presence of islet-cell autoantibodies3,5 — and the results of studies in laboratory rats and mice with spontaneous diabetes — led to clinical trials of methods to prevent or delay the clinical onset of the disease.11,12 The administration of parenteral insulin was effective in the prevention of diabetes in the BioBreeding (BB) rat and the nonobese diabetic (NOD) mouse, but the strategy did not prevent the onset of the disease in first-degree relatives of patients with type 1 diabetes who had tested positive for the islet-cell autoantibody.11 Likewise, although nicotinamide prevented diabetes in the NOD mouse, it was ineffective in a controlled trial in humans.12
The study by Keymeulen et al. was based on both experimental animal models and clinical data suggesting that CD3 monoclonal antibodies might affect autoimmune diabetes. Preclinical studies with CD3 monoclonal antibodies were highly effective in the NOD mouse. The study by Keymeulen et al. was also preceded by a placebo-controlled trial in 24 patients with new-onset type 1 diabetes in which another type of humanized CD3 monoclonal antibody was used.13 The treatment effect on insulin responsiveness lasted for at least 12 months after diagnosis.13 The mechanisms of action remain unclear, but it is speculated that induction of CD8+ T cells and perhaps so-called regulatory CD4+CD25+ T cells might be of importance.
Two aspects of the present study are particularly important and will have implications for future attempts to treat type 1 diabetes with CD3 monoclonal antibodies or similar agents. The first is safety. Is it an acceptable risk that the ChAglyCD3 antibody was associated with an influenzalike syndrome and symptoms of Epstein–Barr viral mononucleosis? The long-term effects of this treatment and the question of whether the induction of virus-antigen–specific CD8+ T cells was important to the improved beta-cell function must be determined.
Another important aspect of the study by Keymeulen et al. is the finding that the ChAglyCD3 antibody was effective only in a subgroup of patients — those among the 80 patients who initially had increased residual beta-cell function (at or above the 50th percentile). Studies that have analyzed the age of patients at the onset of type 1 diabetes, the residual beta-cell function, the distribution of HLA genotypes, and autoantibody positivity suggest that the older the patient, the more C peptide is produced at the time of clinical diagnosis and the fewer high-risk HLA genotypes are present.14 None of these factors appeared to be important in the outcome of the present study, but it is likely that many more teenagers with new-onset diabetes will need to be studied. An additional group that merits further investigation is patients with type 2 diabetes and GAD65 autoantibody, identified as so-called latent autoimmune diabetes in adults.4
The fact the ChAglyCD3 antibody appears effective only when substantial function of residual beta cells is present may limit its applicability. On the other hand, the effect of the ChAglyCD3 antibody may signify that a T-cell–dependent destructive process has to be active before a treatment effect is achieved. If the beta-cell killing has gone too far, there is no point in injecting the CD3 monoclonal antibody. Provided that the treatment is safe, it may be reasonable to consider therapy with CD3 monoclonal antibody for patients with a genetic risk of type 1 diabetes who test positive for islet autoantibody. Screening to detect such patients is carried out by the TrialNet network (www.diabetestrialnet.org/hindex.html), sponsored by the National Institutes of Health, and studied in detail in the TEDDY trial (The Environmental Determinants of Diabetes in the Young; www.teddystudy.org).
The demonstration that the ChAglyCD3 antibody was effective primarily in patients with substantial residual beta-cell function suggests that it may be necessary to increase the efficacy of immunotherapy for type 1 diabetes. A recent phase 2 study suggests that the treatment of latent autoimmune diabetes in adults with alum-formulated GAD65 is safe and may also have a beneficial effect on fasting C-peptide levels.15 If CD3 monoclonal antibodies are shown to be safe, perhaps their use in combination with agents for inducing immune tolerance could lead to improved therapies for type 1 diabetes.
Source Information
From the Department of Medicine, University of Washington, Seattle.
References
Keymeulen B, Vandemeulebroucke E, Ziegler AG, et al. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med 2005;352:2598-2608.
Kent SC, Chen Y, Bregoli L, et al. Expanded T cells from pancreatic lymph nodes of type 1 diabetic subjects recognize an insulin epitope. Nature 2005;435:224-228.
Krischer JP, Cuthbertson DD, Yu L, et al. Screening strategies for the identification of multiple antibody-positive relatives of individuals with type 1 diabetes. J Clin Endocrinol Metab 2003;88:103-108.
Falorni A, Brozzetti A. Diabetes-related antibodies in adult diabetic patients. Best Pract Res Clin Endocrinol Metab 2005;19:119-133.
Notkins AL, Lernmark ?. Autoimmune type 1 diabetes: resolved and unresolved issues. J Clin Invest 2001;108:1247-1252.
Pundziute-Lycka A, Dahlquist G, Nystrom L, et al. The incidence of type I diabetes has not increase but shifted to a younger age at diagnosis in the 0-34 years group in Sweden 1983-1998. Diabetologia 2002;45:783-791.
Skyler JS, Marks JB. Immune intervention in type 1 diabetes mellitus. Diabetes Rev 1993;1:15-42.
The Canadian-European Randomized Control Trial Group. Cyclosporin-induced remission of IDDM after early intervention: association of 1 yr of cyclosporin treatment with enhanced insulin secretion. Diabetes 1988;37:1574-1582.
Bougneres PF, Carel JC, Castano L, et al. Factors associated with early remission of type 1 diabetes in children treated with cyclosporine. N Engl J Med 1988;318:663-670.
Parving HH, Tarnow L, Nielsen FS, et al. Cyclosporine nephrotoxicity in type 1 diabetic patients: a 7-year follow-up study. Diabetes Care 1999;22:478-483.
Diabetes Prevention Trial-Type 1 Diabetes Study Group. Effects of insulin in relatives of patients with type 1 diabetes mellitus. N Engl J Med 2002;346:1685-1691.
Gale EA, Bingley PJ, Emmett CL, Collier T. European Nicotinamide Diabetes Intervention Trial (ENDIT): a randomised controlled trial of intervention before the onset of type 1 diabetes. Lancet 2004;363:925-931.
Herold KC, Hagopian W, Auger JA, et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med 2002;346:1692-1698.
Graham J, Hagopian WA, Kockum I, et al. Genetic effects on age-dependent onset and islet cell autoantibody markers in type 1 diabetes. Diabetes 2002;51:1346-1355.(?ke Lernmark, Med.Dr.)