liu.seSearch for publications in DiVA
Change search
ReferencesLink to record
Permanent link

Direct link
Nicotinamide reduces high secretion of IFN-γ in high-risk relatives even though it does not prevent type 1 diabetes
Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics.
Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics.
2006 (English)In: Journal of Interferon and Cytokine Research, ISSN 1079-9907, Vol. 26, no 4, 207-213 p.Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
2006. Vol. 26, no 4, 207-213 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-34818DOI: 10.1089/jir.2006.26.207Local ID: 23430OAI: diva2:255666
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2010-01-25
In thesis
1. Immunological profile and aspects of immunotherapy in type 1 diabetes
Open this publication in new window or tab >>Immunological profile and aspects of immunotherapy in type 1 diabetes
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2010. 82 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1161
National Category
urn:nbn:se:liu:diva-52139 (URN)978-91-7393-467-1 (ISBN)
Public defence
2010-01-14, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Available from: 2010-01-24 Created: 2009-12-07 Last updated: 2010-01-25Bibliographically approved
The record could not be found. The reason may be that the record is no longer available or you may have typed in a wrong id in the address field.

Open Access in DiVA

No full text

Other links

Publisher's full text

Search in DiVA

By author/editor
Hedman Hjorth, MariaLudvigsson, JohnnyFaresjö, Maria
By organisation
Faculty of Health SciencesPediatricsDepartment of Paediatrics in Linköping
In the same journal
Journal of Interferon and Cytokine Research
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 80 hits
ReferencesLink to record
Permanent link

Direct link