Immunintervention bei neu diagnostiziertem Typ-1-Diabetes - immer noch nur im Rahmen von Studien möglich

Zusammenfassung

Der Erhalt einer körpereigenen Restproduktion von Insulin auch nach der klinischen Manifestation eines Typ-1-Diabetes (T1D) trägt wesentlich zu einer besseren Blutzuckereinstellung und zur Verhinderung diabetischer Folgeerkrankungen bei.

Diese Übersicht stellt Studien zur Immunintervention bei neumanifestem T1D dar. Primärer Endpunkt ist der Erhalt der Betazell-Reserve, gemessen am basalen und stimulierten C-Peptid. Sekundäre Endpunkte umfassen HbA_1c, Insulinbedarf, Nüchternblutzucker, sowie das zelluläre und humorale Immunmonitoring. 1) In München und Mailand werden derzeit im Rahmen des Verbundes Type 1 Diabetes TrialNet die aus der Transplantationsmedizin bekannten Stoffe Mycophenolat mofetil und Daclizumab (MMF-DZB) kombiniert. 2) In einer weiteren TrialNet-Studie soll, beginnend in diesem Jahr, mit Rituximab erstmals ein Wirkstoff bei T1D getestet werden, der B-Zellen depletiert. 3) In Belgien, Paris und München werden 80 Teilnehmer einer Phase II-Studie mit dem CD3-Antikörper ChAgly CD3 bereits im vierten Jahr nachbeobachtet. Ähnliche Studien sollen in Kürze folgen. 4) Die Wirksamkeit des synthetischen Peptids DiaPep277 wird derzeit in einer Phase III Studie an 400 Teilnehmern in elf Ländern verifiziert. 5) Eine Phase II Studie mit dem alterierten Peptidliganden APL-NBI-6024 zeigte keinen Effekt auf die Betazell-Restfunktion. 6) In München läuft eine Studie zur Immunintervention mit 1,25-Dihydroxy-Vitamin D3 mit 40 Teilnehmern.

Abstract

Even after clinical manifestation of type 1 diabetes (T1D), there is still residual secretion of endogenous insulin which essentially helps to maintain better metabolic control and to prevent complications.

This review describes intervention trials in newly diagnosed T1D. Primary endpoint is the preservation of the beta cell reserve, indicated by basal and stimulated C-peptide. Secondary endpoints include HbA_1c levels, insulin requirements, fasting blood glucose levels, and monitoring of cellular and humoral immune responses. 1) As a part of the Type 1 Diabetes TrialNet Network, a study performed in Munich and Milan combines mycophenolate mofetil and daclizumab (MMF-DZB). Both drugs are known from transplant medicine. 2) In another TrialNet study beginning this year, an agent depleting B-cells (rituximab) will be investigated in T1D for the first time. 3) In Belgium, Paris and Munich, 80 participants in a phase II study with the anti-CD3 antibody ChAgly CD3 have now been followed-up for nearly 4 years. Further studies with similar drugs have already been in preparation. 4) The effectiveness of the synthetic peptide DiaPep277 is being verified in a phase III study including 400 participants in 11 countries. 5) A phase II trial with the altered peptide ligand APL-NBI-6024 did not show any effect on betacell residual function. 6) In Munich, a trial tests the immunointervention with 1,25-dihydroxyvitamin D3 in 40 subjects.

Diabetes mellitus - Immunsuppression - Immunmodulation - Betazellfunktion - C-Peptid

Diabetes mellitus - immunosuppression - immunomodulation - beta cell function - C-peptide

Literatur

• 1 Bottazzo G F, Dean B M, McNally J M, MacKay E H, Swift P G, Gamble D R. In situ characterization of autoimmune phenomena and expression of HLA molecules in the pancreas in diabetic insulitis.  N Engl J Med. 1985;  313 353-360
• 2 Itoh N, Hanafusa T, Miyazaki A. et al . Mononuclear cell infiltration and its relation to the expression of major histocompatibility complex antigens and adhesion molecules in pancreas biopsy specimens from newly diagnosed insulin-dependent diabetes mellitus patients.  J Clin Invest. 1993;  92 2313-2322
• 3 Foulis 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;  29 267-274
• 4 The Diabetes Control and Complications Trial Research G roup. Effect of intensive therapy on residual b-cell function patients with type 1 diabetes in the diabetes control a complications trial. A randomized, controlled trial.  Ann Intern Med. 1998;  128 517-523
• 5 Kolb H, Gale E AM. Does partial preservation of residual beta-cell function justify immune intervention in recent onset Type I diabetes?.  Diabetologia. 2001;  44 1349-1353
• 6 Schnell O, Eisfelder B, Standl E, Ziegler A G. High-Dose Intravenous Insulin Infusion Versus Intensive Insulin Treatment in Newly Diagnosed IDDM.  Diabetes. 1997;  46 1607-1611
• 7 Shah S C, Malone J I, Simpson N E. A randomized trial of intensive insulin therapy in newly diagnosed insulin-dependent diabetes mellitus.  N Engl J Med. 1989;  320 550-554
• 8 Martin S, Schernthaner G, Nerup J. et al . Follow-up of cyclosporin. A treatment in type 1 (insulin-dependent) diabetes mellitus: lack of long-term effects.  Diabetologia. 1991;  34 429-434
• 9 Assan R, Feutren G, Debray-Sachs M. et al . Metabolic and immunological effects of cyclosporin in recently diagnosed type 1 diabetes mellitus.  Lancet. 1985;  1 67-71
• 10 Gregori S, Giarratana N, Smiroldo S, Uskokovic M, Adorini L. A 1α,25-Dihydroxyvitamin D₃ Analog Enhances Regulatory T-Cells and Arrests Autoimmune Diabetes in NOD Mice.  Diabetes. 2002;  51 1367-1374
• 11 Jones E L, Epinette W W, Hackney V C, Menendez L, Frost P. Treatment of psoriasis with oral mycophenolic acid.  Journal of Investigative Dermatology. 1975;  65 537-542
• 12 Schiff M. Emerging treatments for rheumatoid arthritis.  American Journal of Medicine. 1997;  102 1A 11S-15S
• 13 Bielekova B, Richert N, Howard T. et al . Humanized anti-CD25 (daclizumab) inhibits disease activity in multiple sclerosis patients failing to respond to interferon.  PNAS. 2004;  101 8705-8708
• 14 Hao L, Chan S M, Lafferty K. Mycophenolate mofetil can prevent the development of diabetes in BB Rats.  Annals of the New York Academy of Sciences. 1993;  696 328-332
• 15 Hao L, Calcinaro F, Gill R G, Eugui E M, Allison A C, Lafferty K J. Facilitation of Specific Tolerance Induction in Adult Mice by RS-61 443.  Transplantation. 1992;  53 590-595
• 16 Allen 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.  Diabetes Care. 1999;  22 1703-1707
• 17 Chase H P, Butler-Simon N, Garg S, McDuffie M, Hoops S L, O'Brien D. A trial of nicotinamide in new-onset type I (insulin-dependent) diabetes mellitus.  Diabetologia. 1990;  33 444-446
• 18 Roep B O. The role of T-cells in the pathogenesis of Type 1 diabetes: from cause to cure.  Diabetologia. 2003;  46 305-321
• 19 Hummel M, Ziegler A G. Prädiktion des Typ-1-Diabetes.  Diabetes, Stoffwechsel und Herz. 2006;  15 55-64
• 20 Davidson A, Diamond B. Autoimmune diseases.  N Engl J Med. 2001;  345 340-350
• 21 Noorchashm H, Lieu Y K, Noorchashm N. et al . I-Ag7-mediated antigen presentation by B lymphocytes is critical in overcoming a checkpoint in T cell tolerance to islet beta cells of nonobese diabetic mice.  J Immunol. 1999;  163 743-750
• 22 Serreze D V, Silveira P A. The role of B lymphocytes as key antigen-presenting cells in the development of T cell-mediated autoimmune type 1 diabetes.  Curr Dir Autoimmun. 2003;  6 212-227
• 23 Takemura S, Klimiuk P A, Braun A, Goronzy J J, Weyand C M. T cell activation in rheumatoid synovium is B cell dependent.  J Immunol. 2001;  167 4710-4718
• 24 Zaja F, Iacona I, Masolini P. et al . B-cell depletion with rituximab as treatment for immune hemolytic anemia and chronic thromobocytopenia.  Haematolgica. 2002;  87 189-195
• 25 Zaja F, Russo D, Fuga G, Perella G, Baccarani M. Rituximab for myasthenia gravis developing after bone marrow transplant.  Neurology. 2000;  55 1062-1063
• 26 Edwards J C, Cambridge G. Sustained improvement in rheumatoid arthritis following a protocol designed to deplete B-lymphocytes.  Rheumatology. 2001;  40 205-211
• 27 Specks U, Fervenza F C, McDonald T J, Hogan M C. Response of Wegener's granulomatosis to anti-CD20 chimeric monoclonal antibody therapy.  Arthritis Rheum. 2001;  44 2836-2840
• 28 Nadler L M, Ritz J, Hardy R, Pesando J M, Schlossman S F, Stashenko P. A unique cell surface antigen identifying lymphoid malignancies of B cell origin.  J Clin Invest. 1981;  67 134-140
• 29 McLaughlin P, Grillo-Lopez A, Link B K. et al . Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program.  J Clin Oncol. 1998;  16 2825-2833
• 30 Vieira C A, Agarwal A, Book B K. et al . Rituximab for reduction of anti-HLA antibodies in patients awaiting renal transplantation: 1. Safety, pharmocodynamics, and pharmacokinetics.  Transplantation. 2004;  77 542-548
• 31 Agarwal A, Vieira C A, Book B K. et al . Rituximab, anti-CD20, induces in vivo cytokine release but does not impair ex vivo T-cell responses.  Am J Transplant. 2004;  4 1357-1360
• 32 van der Kolk L E, Baars J W, Prins M H, van Oers M HJ. Rituximab treatment results in impaired secondary humoral immune responsiveness.  Blood. 2002;  100(6) 2257-2259
• 33 Chatenoud L, Primo J, Bach J F. CD3 antibody-induced dominant self tolerance in overtly diabetic NOD mice.  J Immunol. 1997;  158 2947-2954
• 34 Walter M, Ziegler A G. Anti-CD3-Antikörper reduzieren langfristig den Insulinbedarf bei neumanifestem Typ-1-Diabetes.  Diabetes und Stoffwechsel. 2005;  14 219-220
• 35 Keymeulen B, Vandemeulebroucke E, Ziegler A G. et al . Insulin Needs after CD3-Antibody Therapy in New-Onset Type 1 Diabetes.  N Engl J Med. 2005;  352 2598-2608
• 36 Bonner-Weir S, Weir G C. New sources of pancreatic beta-cells.  Nat Biotechnol. 2005;  23(7) 857-861
• 37 Abulafia-Lapid R, Elias D, Raz I, Keren-Zur Y, Atlan H, Cohen I R. T-cell responses of type I diabetes patients and healthy individuals to human hsp60 and its peptides.  J Autoimmun. 1999;  12 121-129
• 38 Raz I, Elias D, Avron A, Tamir M, Metzger M, Cohen I R. β-cell function in new-onset type 1 diabetes and immunomodulation with a heat-shock protein peptide (DiaPep277): a randomised, double-blind, phase II trial.  Lancet. 2001;  358 1749-1753
• 39 David D A, Gaur A, Jin L. Immunological Characterization and Therapeutic Activity of an Altered-Peptide-Ligand, NBI-6024, Based on the Immunodominant Type 1 Diabetes Autoantigen Insulin B-Chain (9 - 23) Peptide.  Diabetes. 2002;  51 2126-2134
• 40 Alleva D G, Maki R A, Putnam A L. et al . Immunomodulation in Type 1 diabetes by NBI-6024, an Altered Peptide Ligand of the Insulin B_{(9 - 23)} Epitope.  Scand J Immunol. 2006;  63 59-69
• 41 Mathieu C, Gysemans C, Giulietti A, Bouillon R. Vitamin D and diabetes.  Diabetologia. 2005;  48 1247-1257
• 42 Baumgartl H J, Standl E, Schmidt-Gayk H, Kolb H J, Janka H U, Ziegler A G. Changes of vitamin D3 serum concentrations at the onset of immune-mediated type 1 (insulin-dependent) diabetes mellitus.  Diabetes Res. 1991;  16 145-148
• 43 Pozzilli P, Manfrini S, Crino A. et al . Low Levels of 25-hydroxyvitamin D3 and 1,25-di- hydroxyvitamin D3 in Patients with Newly Diagnosed Type 1 Diabetes.  Horm Metab Res. 2005;  37 680-683
• 44 Riachy R, Vandewalle B, Moerman E. et al . 1,25-di-hydroxyvitamin D3 protects human pancreatic islets against cytokine-induced apoptosis via down-regulation of the fas receptor.  Apoptosis. 2006;  11 151-159