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Immunological profile and aspects of immunotherapy in type 1 diabetes
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
2010 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Type 1 diabetes (T1D) is a chronic, autoimmune disease caused by a T cell mediated attack on the insulin producing pancreatic ß-cells. Even though reasonable quality of life can be acquired with modern insulin therapy, prevention of acute and late serious complications is facilitated by preservation of residual insulin secretion. Preventing β-cell destruction is therefore an important goal of T1D therapy. Characterisation of immunological changes in the course of T1D is essential for understanding the underlying pathogenic mechanisms and for evaluating the efficacy of therapeutic intervention.

 

This thesis aimed to study the immune profile in individuals at increased risk of T1D and in patients diagnosed with the disease. In addition, the immunological effects of treatment with the B vitamin, Nicotinamide, and by antigen-specific immunotherapy using GAD65, have been studied in high-risk individuals and in T1D patients, respectively.

We have found that individuals at high risk of T1D had an increased T helper (Th) 1 like immune profile, defined by high secretion of interferon (IFN) -γ. At the time of clinical onset of T1D, the Th1 dominance was diminished. We further demonstrate that children with newly diagnosed T1D had a suppressed Th1 like profile, detected by chemokine and chemokine receptor profile. This was accompanied by an induced population of CCR7+ and CD45RA+ naïve, CD8+cytotoxic T (Tc) cells and a reduced CD45RO+ memory Tc cell pool.

 

It has previously been shown that oral Nicotinamide had no clinical effect in prevention of T1D. However, we found that the treatment was associated with a decreased secretion of IFN-γ. We have previously shown that subcutaneous injections with GAD-alum in T1D children induced a better preservation of endogenous insulin secretion compared with placebo. Here, we demonstrate that the treatment induced an early antigen-specific Th2 and regulatory immune profile. After a few months, and still after more than two years, the recall response to GAD65 was characterised by a broader range of cytokines. GAD-alum treatment also induced a GAD65-specific CD4+CD25highFOXP3+ cell population and reduced the levels of CD4+CD25+ cells.

 

In conclusion, a Th1 like immune profile in pre-diabetic individuals indicates an imbalance of the immune system. At time of clinical onset, and in the period afterwards, reduction of the Th1 associated immune response could be an effect of a suppressed destructive process, selective recruitment of effector T cells to the pancreas or a defective immune regulation. The protective effect of GAD-alum in T1D children seems to be mediated by an early skewing of GAD65-induced responses towards a Th2 phenotype. Further, induction of GAD65-specific T cells with regulatory characteristics might be able to suppress autoreactive responses and inflammation in the pancreas.

Ort, förlag, år, upplaga, sidor
Linköping: Linköping University Electronic Press , 2010. , s. 82
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1161
Nationell ämneskategori
Immunologi
Identifikatorer
URN: urn:nbn:se:liu:diva-52139ISBN: 978-91-7393-467-1 (tryckt)OAI: oai:DiVA.org:liu-52139DiVA, id: diva2:279876
Disputation
2010-01-14, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (Svenska)
Opponent
Handledare
Tillgänglig från: 2010-01-24 Skapad: 2009-12-07 Senast uppdaterad: 2010-01-25Bibliografiskt granskad
Delarbeten
1. Nicotinamide reduces high secretion of IFN-γ in high-risk relatives even though it does not prevent type 1 diabetes
Öppna denna publikation i ny flik eller fönster >>Nicotinamide reduces high secretion of IFN-γ in high-risk relatives even though it does not prevent type 1 diabetes
2006 (Engelska)Ingår i: Journal of Interferon and Cytokine Research, ISSN 1079-9907, E-ISSN 1557-7465, Vol. 26, nr 4, s. 207-213Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Type 1 diabetes (T1D) is an autoimmune disease suggested to be of a T helper (Th)1-like origin. This study aimed to investigate the Th1-like and Th2-like profile in high-risk individuals during the prediabetic phase and the immunologic effect of treatment with nicotinamide. High-risk first-degree relatives of T1D patients participating in the European Nicotinamide Diabetes Intervention Trial (ENDIT) were treated with either nicotinamide or placebo. Peripheral blood mononuclear cells (PBMC) were obtained during the prediabetic phase and close to the onset of manifest T1D and from nondiabetic high-risk individuals. Using the sensitive enzyme-linked immunospot (ELISPOT) technique to distinguish Th1-like from Th2-like lymphocytes, secretion of interferon-γ (IFN-γ) and interleukin-4 (IL-4) was analyzed from PBMCs spontaneously and after in vitro stimulation with the diabetes-associated autoantigens, glutamic acid decarboxylase 65 (GAD65, protein and peptide, aa 247-279), recombinant tyrosine phosphatase (IA-2), and heat shock protein (HSP, aa 437-460). High-risk individuals showed high spontaneous as well as autoantigen-induced IFN-γ secretion. Secretion of IFN-γ and the IFN-γ/IL-4 ratio, induced by autoantigens, decreased in individuals developing T1D (p < 0.05), whereas nondiabetic individuals showed an increased IL-4 response (p < 0.05). Thus, a Th1-dominated cytokine profile observed in high-risk individuals inclined toward a diagnosis of diabetes. Nicotinamide caused decreased spontaneous (p = 0.05) and in vitro autoantigen-induced IFN-γ secretion (p < 0.05) and may play a role in immune regulation, even though it has not been shown to prevent T1D. © Mary Ann Liebert, Inc.

Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:liu:diva-34818 (URN)10.1089/jir.2006.26.207 (DOI)23430 (Lokalt ID)23430 (Arkivnummer)23430 (OAI)
Tillgänglig från: 2009-10-10 Skapad: 2009-10-10 Senast uppdaterad: 2017-12-13
2.
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3. Early induction of GAD(65)-reactive Th2 response in type 1 diabetic children treated with alum-formulated GAD(65)
Öppna denna publikation i ny flik eller fönster >>Early induction of GAD(65)-reactive Th2 response in type 1 diabetic children treated with alum-formulated GAD(65)
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2010 (Engelska)Ingår i: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 26, nr 7, s. 559-568Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Background We have previously shown that two injections of 20 mu g alum-formulated glutamic acid decarboxylase 65 (GAD(65)) (GAD-alum; Diamyd (R)) in children with recent-onset type 1 diabetes lead to preservation of residual insulin secretion. In vitro cytokine production at the 15 months follow-up indicated immunomodulation. In the present study, we took advantage of peripheral blood mononuclear cells, cryopreserved during early follow-ups, to investigate whether the immunomodulatory effect of GAD-alum was apparent earlier after treatment, preceding the changes previously reported at 15 months.<p>Methods Peripheral blood mononuclear cells from 70 type 1 diabetic children, randomly assigned GAD-alum (n = 35) or placebo (n = 35), that had been frozen at baseline (n = 27) and after 1 (n = 58), 3 (n = 67) and 9 (n = 66) months, were stimulated in vitro with GAD(65), tyrosine phosphatase-like protein IA-2 peptide, insulin peptide, GAD-alum, alum formulation or phytohaemagglutinin. Interleukin (IL)-5, -6, -10, -12, -13, -17, tumour necrosis factor and interferon-gamma were measured in cell supernatants and serum samples using Luminex. Expression of FOXP3 and transforming growth factor-beta was determined by real-time reverse transcription polymerase chain reaction.</p><p>Results Already 1 month after the first injection, GAD(65)-induced IL-5 and IL-13 together with FOXP3 were enhanced in GAD-alum-treated patients compared to those with placebo. The in vitro response at 3 and 9 months was characterized by a broader range of cytokines in the treated group. Notably, only the T-helper 2-associated cytokines IL-5 and IL-13 together with FOXP3 increased continuously over time.</p><p>Conclusions Treatment with GAD-alum in type 1 diabetic children induced an early T-helper 2 immune enhanced response to GAD(65), followed by a wider spectrum of cytokines at 3 and 9 months. Copyright (C) 2010 John Wiley &amp; Sons, Ltd.</p>

Ort, förlag, år, upplaga, sidor
John Wiley and Sons, 2010
Nyckelord
GAD65, Immunotherapy, Th1/Th2 Immune Response, Immunomodulation, Cytokines
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:liu:diva-52141 (URN)10.1002/dmrr.1126 (DOI)000283399000007 ()
Tillgänglig från: 2009-12-07 Skapad: 2009-12-07 Senast uppdaterad: 2017-12-12
4. GAD-alum treatment induces GAD65-specific CD4+CD25highFOXP3+ cells and reduces CD4+ cell activation in type 1 diabetic patients
Öppna denna publikation i ny flik eller fönster >>GAD-alum treatment induces GAD65-specific CD4+CD25highFOXP3+ cells and reduces CD4+ cell activation in type 1 diabetic patients
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(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nyckelord
GAD65, Immunomodulation, Immunopathology of Type 1 Diabetes
Nationell ämneskategori
Immunologi
Identifikatorer
urn:nbn:se:liu:diva-52140 (URN)
Tillgänglig från: 2009-12-07 Skapad: 2009-12-07

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