Novel type 1 diabetes vaccines, and methods of use

a type 1 diabetes and vaccine technology, applied in the field of new type 1 diabetes vaccines and methods of use, can solve the problems of impaired glucose metabolism with attendant complications, insufficient insulin production, and abnormal oral glucose tolerance tests (ogtts), and achieve the effects of reducing severity or progression, and preventing or delay the onset of t1d

Inactive Publication Date: 2014-09-18
UNIV OF FLORIDA RES FOUNDATION INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0019]In accordance with the subject invention, it has been found that APCs that have been pulsed with bacteria strains can be used to alleviate (delay the onset of and / or reduce the severity or progression of), T1D. In specific embodiments of the subject invention, the administration of DCs that have been pulsed with Lactobacillus strains such as L. johnsonii can prevent or delay the onset of, or reduce the progression of, T1D in an animal model. Specially exemplified herein is the use of Lactobacillus johnsonii N6.2. Vaccination with DCs that have been pulsed with Lactobacillus johnsonii N6.2 conferred T1D resistance to DP rodents. Diabetes resistance in the DP rodents was correlated to a TH17 bias within the mesenteric lymph nodes, which was associated with high levels of IL6 and IL23.

Problems solved by technology

The progressive loss of pancreatic beta cells results in insufficient insulin production and, thus, impaired glucose metabolism with attendant complications.
The factors responsible for T1D are complex and thought to involve a combination of genetic, environmental, and immunologic influences that contribute to the inability to provide adequate insulin secretion to regulate glycemia.
Later, as the disease progresses, the oral glucose tolerance test (OGTT) typically becomes abnormal.
However, similar studies in T1D are limited.
Although insulin administration is effective in achieving some level of euglycemia in most patients, it does not prevent the long-term complications of the disease including ketosis and damage to small blood vessels, which may affect eyesight, kidney function, and blood pressure and can cause circulatory system complications.
Furthermore, despite the enormously deleterious health and economic consequences, and the extensive research effort, there currently is no effective means for controlling the formation of this disease.

Method used

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  • Novel type 1 diabetes vaccines, and methods of use
  • Novel type 1 diabetes vaccines, and methods of use
  • Novel type 1 diabetes vaccines, and methods of use

Examples

Experimental program
Comparison scheme
Effect test

example 1

Diminished Peripheral Th17 Differentiation and APC Frequency is Correlated to T1D Onset

[0077]In order to better understand the relationship betweenTh17 differentiation and T1D onset, IL17 production by stimulated NOD T lymphocytes was compared to that of NOR lymphocytes. Although proliferation and IFNγ production were comparable in activated NOD and NOR peripheral LN suspensions, three-fold more IL17 was produced by NOR lymphocytes (FIG. 1A). Since APC derived IL6 is required for TH17 differentiation, its production was measured in the NOD and NOR LN suspensions. Whereas no IL6 production was detected within NOD LN suspensions, IL6 production was readily observed within the activated NOR LN suspension (FIG. 1A). Together, these data show that in vitro activated LN suspensions from diabetes resistant NOR mice possessed higher levels of Th17 differentiation than pre-diabetic NOD counterparts.

[0078]As differences in Th17 differentiation between NOD and NOR LN suspensions could be due t...

example 2

Lymphocytes in Pancreas of NOD Mice Exhibit Reduced Th17 Bias Compared to those Present in NOR Pancreas

[0081]NOR and NOD mice experience leukocytic infiltrations of the pancreas, however NOR mice are resistant to insulitis and T1D. Since reduced amounts of IL17 were observed in the peripheral LN of NOD mice compared to NOR, differences in Th17 associated factors within the leukocytic infiltrations of the pancreas were studied. Frozen-OCT embedded sections from the pancreases of both strains were generated, which were processed to either generate H&E stains or to measure the presence of Th17 related RNA. Sequential sections were utilized so that infiltrates shown in the H&E histology could be compared to RNA message levels.

[0082]Leukocytic infiltrations were observed in pancreatic H&E stains from both pre-diabetic 12 week old NOD and age-matched NOR mice (FIG. 3A). The NOD pancreas, however, possessed significantly more T lymphocyte infiltration and profound insulitis (as denoted by ...

example 3

NOD and NOR Mice Possess Distinct Th17 Biases in Mesenteric LN which is Correlated to Diverse Microbial Communities

[0085]The mesenteric LN of NOR and NOD mice were examined for distinctions in cytokine profiles.

[0086]Although mesenteric LN cells isolated from NOD mice possessed 50% more CD3 message, IL17 message levels were significantly lower in the NOD mesenteric LN (mLN) compared to the NOR. The Th17 specific transcription factor, RORγt, and surface protein, IL23 receptor (IL23R) were also consistently lower in the NOD mLN (FIG. 4A, 5). Notably, message levels for IL23 (required to sustain the Th17 phenotype), but not IL6 were consistently lower in the mLN of NOD mice compared to NOR (FIG. 5).

[0087]Although lymphocytes present in the gut preferentially track to the pancreatic LN, distinctions in Th17 associated factors were not observed within the pancreatic LN (FIG. 6).

[0088]Together, these data show that pancreas and mLN of spontaneously diabetic NOD mice, possess a significant...

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Abstract

The subject invention provides compositions for alleviating type 1 diabetes (T1D). In preferred embodiments, the compositions comprise an effective amount of one or more antigen presenting cells (APCs) that have been pulsed with one or more bacterial isolates and/or compounds from the isolates. The bacteria used to pulse the APCs are, preferably, those that confer upon the APCs the ability to inhibit the generation of diabetes-promoting T cells. In specific embodiments, these bacteria may be, for example, Eubacteria or Clostridia. In a preferred embodiment, the APCs are dendritic cells (DCs).

Description

CROSS-REFERENCE TO A RELATED APPLICATION[0001]This application claims the benefit of U.S. provisional application Ser. No. 61 / 793,321, filed Mar. 15, 2013, which is incorporated herein by reference in its entirety.BACKGROUND[0002]Diabetes mellitus is a family of disorders characterized by chronic hyperglycemia and the development of long-term vascular complications. This family of disorders includes type 1 diabetes, type 2 diabetes, gestational diabetes, and other types of diabetes.[0003]Immune-mediated (type 1) diabetes (or insulin dependent diabetes mellitus, IDDM, T1D) is a disease of children and adults for which there currently is no adequate means for prevention or cure. Type 1 diabetes, represents approximately 10% of all human diabetes. The disease is characterized by an initial leukocyte infiltration into the pancreas that eventually leads to inflammatory lesions within islets, a process called “insulitis”.[0004]Type 1 diabetes is distinct from non-insulin dependent diabete...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/02A61K39/09A61K39/08
CPCA61K39/0208A61K39/09A61K39/08A61K39/0008A61K2039/58A61P37/00A61P3/10A61K35/15A61K39/02A61K2039/5154A61K2039/5158A61K2039/577
Inventor LARKIN, JOSEPHATKINSON, MARK A.
Owner UNIV OF FLORIDA RES FOUNDATION INC
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