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Online Letters to the Editor

Response to Comment on: Meagher et al. Neutralization of Interleukin-16 Protects Nonobese Diabetic Mice From Autoimmune Type 1 Diabetes by a CCL4-Dependent Mechanism. Diabetes 2010;59:2862–2871

  1. Craig Meagher1,
  2. William Cruikshank2 and
  3. Terry L. Delovitch1
  1. From the 1Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada; and
  2. 2The Pulmonary Center, Boston University, Boston, Massachusetts
  1. Corresponding author: Terry L. Delovitch, del{at}robarts.ca.
Diabetes 2011 Feb; 60(2): e13-e13. https://doi.org/10.2337/db10-1620
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We thank Vendrame and Dotta (1) for their interesting perspective regarding our recently published study investigating the role of interleukin-16 (IL-16) in the development of insulitis and type 1 diabetes in female NOD mice (2). On the basis of previous studies correlating suboptimal activation of caspase-3 with the development of autoimmunity in the clinical setting (3,4), they propose a similar condition might exist in NOD mice, resulting in defective secretion of mature IL-16. Although we have not directly examined this possibility, it must be considered that many studies have wrestled with the difficulty in detecting secreted IL-16 in several mouse strains used to examine inflammatory responses (2,5). This likely reflects the biology of mature IL-16, which is active at concentrations as low as 10−11 M, and indicates that the low levels of intrapancreatic mature IL-16 detected during the development of insulitis is not restricted only to the NOD genetic background.

However, the notion that caspase-3 activation may be suboptimal in NOD mice is suggested by several articles reporting that T cells in NOD mice exhibit an altered signaling cascade downstream of the T-cell receptor, resulting in a hyporesponsive state of activation and resistance to activation-induced cell death (6–8). Importantly, although it may be that a reduction in caspase-3 activation leads to diminished IL-16 secretion, this correlation has not yet been proven and the level of activated caspase-3 required for cleavage of pro–IL-16 is unknown. Thus, in support of the perspective by Vendrame and Dotta, it is uncertain how a partial deficiency in caspase-3 activation would affect levels of IL-16 secretion; but clearly, based on our results, the level of caspase-3 activation occurring in lymphocytes is sufficient for the secretion of IL-16 and recruitment of T cells needed for disease pathology. Collectively, a partial deficiency in caspase-3 activation may contribute to T-cell resistance to activation-induced cell death, which would enable autoreactive T cells to persist and may also facilitate their recruitment to islets via secretion of mature IL-16.

Acknowledgments

No potential conflicts of interest relevant to this article were reported.

  • © 2011 by the American Diabetes Association.

REFERENCES

  1. ↵
    1. Vendrame F,
    2. Dotta F
    . Comment on: Meagher et al. Neutralization of interleukin-16 protects nonobese diabetic mice from autoimmune type 1 diabetes by a CCL4-dependent mechanism. Diabetes 2010;59:2862–2871 (Letter). Diabetes 2011;60:e12. doi:10.2337/db10-1489
    OpenUrlFREE Full Text
  2. ↵
    1. Meagher C,
    2. Beilke J,
    3. Arreaza G,
    4. et al
    . Neutralization of interleukin-16 protects nonobese diabetic mice from autoimmune type 1 diabetes by a CCL4-dependent mechanism. Diabetes 2010;59:2862–2871
    OpenUrlAbstract/FREE Full Text
  3. ↵
    1. Vendrame F,
    2. Santangelo C,
    3. Misasi R,
    4. et al
    . Defective lymphocyte caspase-3 expression in type 1 diabetes mellitus. Eur J Endocrinol 2005;152:119–125
    OpenUrlAbstract/FREE Full Text
  4. ↵
    1. Vendrame F,
    2. Segni M,
    3. Grassetti D,
    4. et al
    . Impaired caspase-3 expression by peripheral T cells in chronic autoimmune thyroiditis and in autoimmune polyendocrine syndrome-2. J Clin Endocrinol Metab 2006;91:5064–5068
    OpenUrlCrossRefPubMed
  5. ↵
    1. Yoshimoto T,
    2. Wang CR,
    3. Yoneto T,
    4. Matsuzawa A,
    5. Cruikshank WW,
    6. Nariuchi H
    . Role of IL-16 in delayed-type hypersensitivity reaction. Blood 2000;95:2869–2874
    OpenUrlAbstract/FREE Full Text
  6. ↵
    1. Salojin KV,
    2. Zhang J,
    3. Madrenas J,
    4. Delovitch TL
    . T-cell anergy and altered T-cell receptor signaling: effects on autoimmune disease. Immunol Today 1998;19:468–473
    OpenUrlCrossRefPubMedWeb of Science
    1. Salojin K,
    2. Zhang J,
    3. Cameron M,
    4. et al
    . Impaired plasma membrane targeting of Grb2-murine son of sevenless (mSOS) complex and differential activation of the Fyn-T cell receptor (TCR)-zeta-Cbl pathway mediate T cell hyporesponsiveness in autoimmune nonobese diabetic mice. J Exp Med 1997;186:887–897
    OpenUrlAbstract/FREE Full Text
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    1. Arreaza G,
    2. Salojin K,
    3. Yang W,
    4. et al
    . Deficient activation and resistance to activation-induced apoptosis of CD8+ T cells is associated with defective peripheral tolerance in nonobese diabetic mice. Clin Immunol 2003;107:103–115
    OpenUrlCrossRefPubMed
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Response to Comment on: Meagher et al. Neutralization of Interleukin-16 Protects Nonobese Diabetic Mice From Autoimmune Type 1 Diabetes by a CCL4-Dependent Mechanism. Diabetes 2010;59:2862–2871
Craig Meagher, William Cruikshank, Terry L. Delovitch
Diabetes Feb 2011, 60 (2) e13; DOI: 10.2337/db10-1620

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Response to Comment on: Meagher et al. Neutralization of Interleukin-16 Protects Nonobese Diabetic Mice From Autoimmune Type 1 Diabetes by a CCL4-Dependent Mechanism. Diabetes 2010;59:2862–2871
Craig Meagher, William Cruikshank, Terry L. Delovitch
Diabetes Feb 2011, 60 (2) e13; DOI: 10.2337/db10-1620
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