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Aerosol insulin induces regulatory CD8 gamma delta T cells that prevent murine insulin-dependent diabetes.

Harrison LC, Dempsey-Collier M, Kramer DR, Takahashi K - J. Exp. Med. (1996)

Bottom Line: Insulin-treated mice had increased circulating antibodies to insulin, absent splenocyte proliferation to the major epitope, insulin B chain amino acids 9-23, which was associated with increased IL-4 and particularly IL-10 secretion, and reduced proliferation to glutamic acid decarboxylase, another islet autoantigen.These findings reveal a novel mechanism for suppressing cell-mediated autoimmune disease.Induction of regulatory CD8 gamma delta T cells by aerosol insulin is a therapeutic strategy with implications for the prevention of human IDDM.

View Article: PubMed Central - PubMed

Affiliation: Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Parkville, Australia.

ABSTRACT
Cellular immune hyporesponsiveness can be induced by the presentation of soluble protein antigens to mucosal surfaces. Most studies of mucosa-mediated tolerance have used the oral route of antigen delivery and few have examined autoantigens in natural models of autoimmune disease. Insulin is an autoantigen in humans and nonobese diabetic (NOD) mice with insulin-dependent diabetes mellitus (IDDM). When we administered insulin aerosol to NOD mice after the onset of subclinical disease, pancreatic islet pathology and diabetes incidence were both significantly reduced. Insulin-treated mice had increased circulating antibodies to insulin, absent splenocyte proliferation to the major epitope, insulin B chain amino acids 9-23, which was associated with increased IL-4 and particularly IL-10 secretion, and reduced proliferation to glutamic acid decarboxylase, another islet autoantigen. The ability of splenocytes from insulin-treated mice to suppress the adoptive transfer of diabetes to nondiabetic mice by T cells of diabetic mice was shown to be caused by small numbers of CD8 gamma delta T cells. These findings reveal a novel mechanism for suppressing cell-mediated autoimmune disease. Induction of regulatory CD8 gamma delta T cells by aerosol insulin is a therapeutic strategy with implications for the prevention of human IDDM.

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Related in: MedlinePlus

Aerosol insulin induces CD8 T cells that suppress the transfer of diabetes. 6–9-wk-old NOD male mice (n = 16 per group) were injected  with pooled splenocytes from recently diabetic 14–19-wk-old females, together with either unfractionated (A) or fractionated (B–E) splenocytes from  aerosol insulin– or OVA-treated NOD females, and their incidence of diabetes was subsequently monitored. In the experiment shown, aerosol donor  mice had been treated for 10 consecutive days and then weekly from 49 d of age, and were normoglycemic when killed at 156 d of age.
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Figure 1: Aerosol insulin induces CD8 T cells that suppress the transfer of diabetes. 6–9-wk-old NOD male mice (n = 16 per group) were injected with pooled splenocytes from recently diabetic 14–19-wk-old females, together with either unfractionated (A) or fractionated (B–E) splenocytes from aerosol insulin– or OVA-treated NOD females, and their incidence of diabetes was subsequently monitored. In the experiment shown, aerosol donor mice had been treated for 10 consecutive days and then weekly from 49 d of age, and were normoglycemic when killed at 156 d of age.

Mentions: As mucosal tolerance has been associated with the appearance of “regulatory” cells in the spleen (16, 18, 20–23), we asked if aerosol insulin– induced regulatory cells that could inhibit the adoptive transfer of diabetes by pathogenic effector T cells. In the classic adoptive transfer model (37; see Fig. 3), spleen cells from diabetic NOD female mice transferred intravenously to young, irradiated, nondiabetic, syngenic male or female recipients cause clinical diabetes in the majority within 4 wk. When we coinjected 2 × 107 spleen cells from older, diabetic mice with an equal number of spleen cells from aerosol OVA mice, the majority of young recipients developed diabetes within 4–5 wk; in contrast, after coinjection with spleen cells from aerosol insulin mice, only a minority developed diabetes (Fig. 1 A). Diabetes incidence was suppressed by ⩾75% in six separate experiments with either splenocytes or nylon wool–nonadherent splenocytes (enriched for T cells) from aerosol insulin mice.


Aerosol insulin induces regulatory CD8 gamma delta T cells that prevent murine insulin-dependent diabetes.

Harrison LC, Dempsey-Collier M, Kramer DR, Takahashi K - J. Exp. Med. (1996)

Aerosol insulin induces CD8 T cells that suppress the transfer of diabetes. 6–9-wk-old NOD male mice (n = 16 per group) were injected  with pooled splenocytes from recently diabetic 14–19-wk-old females, together with either unfractionated (A) or fractionated (B–E) splenocytes from  aerosol insulin– or OVA-treated NOD females, and their incidence of diabetes was subsequently monitored. In the experiment shown, aerosol donor  mice had been treated for 10 consecutive days and then weekly from 49 d of age, and were normoglycemic when killed at 156 d of age.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196363&req=5

Figure 1: Aerosol insulin induces CD8 T cells that suppress the transfer of diabetes. 6–9-wk-old NOD male mice (n = 16 per group) were injected with pooled splenocytes from recently diabetic 14–19-wk-old females, together with either unfractionated (A) or fractionated (B–E) splenocytes from aerosol insulin– or OVA-treated NOD females, and their incidence of diabetes was subsequently monitored. In the experiment shown, aerosol donor mice had been treated for 10 consecutive days and then weekly from 49 d of age, and were normoglycemic when killed at 156 d of age.
Mentions: As mucosal tolerance has been associated with the appearance of “regulatory” cells in the spleen (16, 18, 20–23), we asked if aerosol insulin– induced regulatory cells that could inhibit the adoptive transfer of diabetes by pathogenic effector T cells. In the classic adoptive transfer model (37; see Fig. 3), spleen cells from diabetic NOD female mice transferred intravenously to young, irradiated, nondiabetic, syngenic male or female recipients cause clinical diabetes in the majority within 4 wk. When we coinjected 2 × 107 spleen cells from older, diabetic mice with an equal number of spleen cells from aerosol OVA mice, the majority of young recipients developed diabetes within 4–5 wk; in contrast, after coinjection with spleen cells from aerosol insulin mice, only a minority developed diabetes (Fig. 1 A). Diabetes incidence was suppressed by ⩾75% in six separate experiments with either splenocytes or nylon wool–nonadherent splenocytes (enriched for T cells) from aerosol insulin mice.

Bottom Line: Insulin-treated mice had increased circulating antibodies to insulin, absent splenocyte proliferation to the major epitope, insulin B chain amino acids 9-23, which was associated with increased IL-4 and particularly IL-10 secretion, and reduced proliferation to glutamic acid decarboxylase, another islet autoantigen.These findings reveal a novel mechanism for suppressing cell-mediated autoimmune disease.Induction of regulatory CD8 gamma delta T cells by aerosol insulin is a therapeutic strategy with implications for the prevention of human IDDM.

View Article: PubMed Central - PubMed

Affiliation: Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Parkville, Australia.

ABSTRACT
Cellular immune hyporesponsiveness can be induced by the presentation of soluble protein antigens to mucosal surfaces. Most studies of mucosa-mediated tolerance have used the oral route of antigen delivery and few have examined autoantigens in natural models of autoimmune disease. Insulin is an autoantigen in humans and nonobese diabetic (NOD) mice with insulin-dependent diabetes mellitus (IDDM). When we administered insulin aerosol to NOD mice after the onset of subclinical disease, pancreatic islet pathology and diabetes incidence were both significantly reduced. Insulin-treated mice had increased circulating antibodies to insulin, absent splenocyte proliferation to the major epitope, insulin B chain amino acids 9-23, which was associated with increased IL-4 and particularly IL-10 secretion, and reduced proliferation to glutamic acid decarboxylase, another islet autoantigen. The ability of splenocytes from insulin-treated mice to suppress the adoptive transfer of diabetes to nondiabetic mice by T cells of diabetic mice was shown to be caused by small numbers of CD8 gamma delta T cells. These findings reveal a novel mechanism for suppressing cell-mediated autoimmune disease. Induction of regulatory CD8 gamma delta T cells by aerosol insulin is a therapeutic strategy with implications for the prevention of human IDDM.

Show MeSH
Related in: MedlinePlus