Treatment for insulin dependent diabetes

Abstract

A method for the prevention of insulin dependent (type I) diabetes. The method comprises administration of an antibody, polypeptide or other molecule recognizing VLA-4.

Description

[0001] This application is a continuation-in-part of U.S. patent application Ser. No. 08 / 447,118, filed May 22, 1995, which is a continuation-in-part of U.S. patent application Ser. No. 08 / 029,330, filed Feb. 9, 1993, and of Burkly PCT US94 / 01456, filed Feb. 9, 1994, all of which are incorporated by reference.FIELD OF THE INVENTION [0002] The present invention relates to a treatment for insulin dependent (type-I) diabetes. More particularly, this invention relates to the use of antibodies recognizing the integrin VLA-4 (very late antigen 4) in the prevention of diabetes. BACKGROUND OF THE INVENTION [0003] Insulin dependent diabetes (also termed type-I diabetes and formerly juvenile onset diabetes mellitus) has been classified during the past two decades as a chronic autoimmune disease. In this disorder, cells producing insulin (β cells) within the pancreatic islets are selectively targeted and destroyed by a cellular infiltrate of the pancreas. This inflammatory infiltrate affecting...

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Benefits of technology

[0056] For histological analysis, mice were sacrificed between 2-4 weeks post-transfer as described in this Example and pancreata harvested in 10% formalin buffered saline for paraffin-embedded sections which were stained with hematoxylin and eosin (H&E) for histology. Degree of insulitis was scored as follows: Grade 0: no insulitis [islet devoid of inflammation]; Grade I: peri-insulitis [inflammatory mononuclear cells located peripheral to the islet]; Grade II: <25% infiltrated [<25% of the islet interior contains lymphocytic inflammatory cells]; Grade III: 25-50% infiltrated [lymphocytic infiltration]; Grade IV: >50% infiltrated. The percent of islets in each Grade was then calculated relative to the total number of islets examined. Histologic sections were examined and scored for the degree of insulitis following the adoptive transfer of NOD splenocytes with and without anti-VLA-4 mAb treatment and the results tabulated. Specifically, the frequency of uninfiltrated islets (Grade 0-I infiltrate) and islets with Grade II-IV insulitis (as described above) were quantitated. For each experimental group, pancreatic sections from n=4-5 mice were scored.

[0057] Pancreatic tissue was recovered from recipients treated with the anti-VLA-4 mAb for various time periods in order to address its effect on the establishment of islet-specific cellular infiltrates. Mice were treated with nonspecific rat IgG2b or R1-2 mAb every 3.5 days through day 14 when sacrificed. Similarly, mice were treated through day 25 and sacrificed after diabetes was diagnosed or on day 26 post transfer. Mice continuously treated with the R1-2 mAb for 14 days post transfer maintain a high frequency (76%) of uninfiltrated islets, with only 24% progressing to grade II-IV insulitis. By contrast those treated with nonspecific rat IgG2b show the reciprocal pattern, with 74% severe insulitis. Likewise, in the mice treated with R1-2 though day 25 (20% diabetic, pancreata isolated from mice reported in FIG. 2), a high frequency (58%) of uninfiltrated islets were preserved, similar to that

Problems solved by technology

Stage I is genetic susceptibility, which is a necessary but insufficient condition for development of the disease.

Because there are multiple molecular pathways for cell adhesion and T cell-activation, it is not possible to predict whether intervention in one or more of these pathways might affect onset or severity of diabetes disease, and, in particular, which of these pathways are crucial or relevant to the disease process.

Federlin and Becker, 1990 [34] suggest, however, that cyclosporin A may not be recommended for general or long-term use because of toxic side effects, at least when given in higher doses.

Within 3 years, however, remissions are almost invariably lost (Castano and Eisenbarth, 1990 [1]).

Treatment protocols after onset of disease are particularly problematic, since, for example, at the time diabetes is diagnosed in humans, insulitis has typically progressed already to a loss of more than 80% of the β cells.

To date, there has been little success, however, in treating human diabetes.

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