Lymphocyte vaccination protects prediabetic non-obese diabetic mice from developing diabetes mellitus

Abstract

Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disorder in which destruction of beta cells in the islets of Langerhans leads to insulin deficiency. This process is believed to be mediated by autoreactive T cells. In a close animal model of IDDM, the non-obese-diabetic (NOD) mouse, more direct evidence is available that autoreactive T lymphocytes are pathogenic, since diabetes can be transferred from diabetic mice to naõ Ève recipients using T lymphocytes alone [1]. Such a mechanism of transfer has also been demonstrated in other animal models of human autoimmune disease, leading to the development of a strategy of disease prevention that exploits this pathogenicity in a manoeuvre termed ªlympho-cyte vaccinationº [2]. Diabetologia (1997) Summary In the therapeutic manoeuvre termed ªlymphocyte vaccinationº, activated lymphocytes capable of transferring an autoimmune disease are instead attenuated and given in vaccine form. We have previously shown that such a therapy administered to non-obese diabetic (NOD) mice at 6 weeks of age prevents diabetes mellitus. To assess whether this therapy has potential clinical relevance, in the present study lymphocyte vaccination was applied in NOD mice in 3 weekly doses commencing in the immediate prediabetic period (age 12 weeks), when insulitis is advanced and diabetes incipient. Of 30 NOD mice receiving active vaccine (composed of attenuated lymphocytes from diabetic NOD mice) 13 (43.3 %) remained non-diabetic to the age of 30 weeks, in comparison with 2 of 30 (6.7 %; p < 0.01) mice receiving a control vaccine (composed of attenuated lymphocytes from non-diabetic NOD/ B10 mice) and 5 of 26 (19.2 %; p < 0.01) mice receiving saline carrier alone. Moreover, in an additional group of 10 NOD mice receiving active vaccine weekly between 12 and 30 weeks, 8 remained diabetes free at the end of the treatment. The most notable effect of the vaccine was that the delay in diabetes onset was accompanied by a reduction in insulitis and in some cases a complete absence of infiltrating lymphocytes at 30 weeks of age. Immunocytochemistry indicated that when present, islet infiltrating lymphocytes in non-diabetic mice that received active vaccine showed significantly reduced staining for interferon-g, compared with the infiltrate seen in diabetic mice receiving the control vaccine or saline. This study demonstrates that the rapid progression to diabetes typically seen in 12-week-old NOD mice can be delayed by lymphocyte vaccination, supporting the possibility that a vaccine composed of attenuated autologous peripheral blood lymphocytes could be effective in high risk first degree relatives of patients with insulin dependent diabetes mellitus. [Diabetologia (1997

Spatial distribution and temporal onset of NF-kB activation and inducible nitric oxide synthase within pancreatic islets in the pre-diabetic stage of genetic, diabetic-prone BB rats: Attenuation by drug intervention decreases inflammatory cell infiltration and incidence of diabetes

“…Histological scoring of pancreas was determined blindly by one of the authors (Dr. Henderson) according to previously established criteria [8] as follows: 0-(no infiltration); 1-(polar-islet infiltration); 2-(peri-islet infiltration); 3-(intra-islet infiltration) and 4-(extensive intraislet infiltration). Immunohistochemical determination of iNOS and NF-kB was performed in deparaffinized sections with or without H & E counterstaining.…”

Atorvastatin Fails to Prevent the Development of Autoimmune Diabetes Despite Inhibition of Pathogenic β-Cell–Specific CD8 T-Cells

“…Female NOD mice were obtained from our breeding colony (13)(14)(15), and studies were performed with approval from the institute's ethical review committee.…”

Spontaneous T-cell proliferation in the non-obese diabetic mouse to a peptide from the unique class II MHC molecule, I-A g7 , which is also protective against the development of autoimmune diabetes

“…The NOD mouse colony at King's College School of Medicine and Dentistry (London, UK) has an incidence of diabetes of approximately 90±95 % at 25 weeks of age in both females and males [15]. Diabetes is diagnosed using urinary glucose testing (values > 8.3 mmol/l on two occasions 72 h apart) and confirmed by blood glucose measurement over 16.7 mmol/l.…”