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Determinant spreading of T helper cell 2 (Th2) responses to pancreatic islet autoantigens.

Tian J, Lehmann PV, Kaufman DL - J. Exp. Med. (1997)

Bottom Line: Surprisingly, induction of antiinflammatory Th2 responses to a single beta cell antigen (betaCA) resulted in the spreading of Th2 cellular and humoral immunity to unrelated betaCAs in an infectious manner and protection from IDDM.The data suggest that both Th1 and Th2 autoimmunity evolve in amplificatory cascades by generating site-specific, but not antigen-specific, positive feedback circuits.Determinant spreading of Th2 responses may be a fundamental mechanism underlying antigen-based immunotherapeutics, explaining observations of infectious tolerance and providing a new theoretical framework for therapeutic intervention.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, California 90095-1735, USA.

ABSTRACT
The nature (Th1 versus Th2) and dynamics of the autoimmune response during the development of insulin-dependent diabetes mellitus (IDDM) and after immunotherapy are unclear. Here, we show in nonobese diabetic (NOD) mice that the autoreactive T cell response starts and spreads as a pure Th1 type autoimmunity, suggesting that a spontaneous Th1 cascade underlies disease progression. Surprisingly, induction of antiinflammatory Th2 responses to a single beta cell antigen (betaCA) resulted in the spreading of Th2 cellular and humoral immunity to unrelated betaCAs in an infectious manner and protection from IDDM. The data suggest that both Th1 and Th2 autoimmunity evolve in amplificatory cascades by generating site-specific, but not antigen-specific, positive feedback circuits. Determinant spreading of Th2 responses may be a fundamental mechanism underlying antigen-based immunotherapeutics, explaining observations of infectious tolerance and providing a new theoretical framework for therapeutic intervention.

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βCA treatment inhibits insulin-dependent diabetes. Neonatal  female NOD mice were treated at days 1 and 3 with 200 μg HEL11–25,  GADp11, GADp35, or GADp6 in IFA and were followed up until they  reached 1 y of age in order to determine the effect of treatment on long-term disease incidence. Two consecutive blood glucose levels of >300  mg/dl was considered disease onset. n = 15 for each group.
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Figure 2: βCA treatment inhibits insulin-dependent diabetes. Neonatal female NOD mice were treated at days 1 and 3 with 200 μg HEL11–25, GADp11, GADp35, or GADp6 in IFA and were followed up until they reached 1 y of age in order to determine the effect of treatment on long-term disease incidence. Two consecutive blood glucose levels of >300 mg/dl was considered disease onset. n = 15 for each group.

Mentions: Furthermore, the GAD peptide–treated NOD mice had significantly reduced long-term disease incidence (∼30% of GAD peptide-treated mice versus 96% of controls developed diabetes over 1 yr (P ⩽0.02); Fig. 2). The lack of complete protection by GAD treatment may be due to the diminution of Th2 responses later in life (11, 18). While the induction of Th2 responses to some nontarget tissue antigens has been associated with protection from autoimmune disease (23, 24), the control nontarget tissue antigens used in this study did not induce Th2 spreading or protection from disease.


Determinant spreading of T helper cell 2 (Th2) responses to pancreatic islet autoantigens.

Tian J, Lehmann PV, Kaufman DL - J. Exp. Med. (1997)

βCA treatment inhibits insulin-dependent diabetes. Neonatal  female NOD mice were treated at days 1 and 3 with 200 μg HEL11–25,  GADp11, GADp35, or GADp6 in IFA and were followed up until they  reached 1 y of age in order to determine the effect of treatment on long-term disease incidence. Two consecutive blood glucose levels of >300  mg/dl was considered disease onset. n = 15 for each group.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199172&req=5

Figure 2: βCA treatment inhibits insulin-dependent diabetes. Neonatal female NOD mice were treated at days 1 and 3 with 200 μg HEL11–25, GADp11, GADp35, or GADp6 in IFA and were followed up until they reached 1 y of age in order to determine the effect of treatment on long-term disease incidence. Two consecutive blood glucose levels of >300 mg/dl was considered disease onset. n = 15 for each group.
Mentions: Furthermore, the GAD peptide–treated NOD mice had significantly reduced long-term disease incidence (∼30% of GAD peptide-treated mice versus 96% of controls developed diabetes over 1 yr (P ⩽0.02); Fig. 2). The lack of complete protection by GAD treatment may be due to the diminution of Th2 responses later in life (11, 18). While the induction of Th2 responses to some nontarget tissue antigens has been associated with protection from autoimmune disease (23, 24), the control nontarget tissue antigens used in this study did not induce Th2 spreading or protection from disease.

Bottom Line: Surprisingly, induction of antiinflammatory Th2 responses to a single beta cell antigen (betaCA) resulted in the spreading of Th2 cellular and humoral immunity to unrelated betaCAs in an infectious manner and protection from IDDM.The data suggest that both Th1 and Th2 autoimmunity evolve in amplificatory cascades by generating site-specific, but not antigen-specific, positive feedback circuits.Determinant spreading of Th2 responses may be a fundamental mechanism underlying antigen-based immunotherapeutics, explaining observations of infectious tolerance and providing a new theoretical framework for therapeutic intervention.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, California 90095-1735, USA.

ABSTRACT
The nature (Th1 versus Th2) and dynamics of the autoimmune response during the development of insulin-dependent diabetes mellitus (IDDM) and after immunotherapy are unclear. Here, we show in nonobese diabetic (NOD) mice that the autoreactive T cell response starts and spreads as a pure Th1 type autoimmunity, suggesting that a spontaneous Th1 cascade underlies disease progression. Surprisingly, induction of antiinflammatory Th2 responses to a single beta cell antigen (betaCA) resulted in the spreading of Th2 cellular and humoral immunity to unrelated betaCAs in an infectious manner and protection from IDDM. The data suggest that both Th1 and Th2 autoimmunity evolve in amplificatory cascades by generating site-specific, but not antigen-specific, positive feedback circuits. Determinant spreading of Th2 responses may be a fundamental mechanism underlying antigen-based immunotherapeutics, explaining observations of infectious tolerance and providing a new theoretical framework for therapeutic intervention.

Show MeSH
Related in: MedlinePlus