Lymphoid hyperplasia, CD45RB(high) to CD45RB(low) T-cell imbalance, and suppression of type I diabetes mellitus result from TNF blockade in nod → NOD-scid adoptive T cell transfer

G. R. Brown, M. D. Silva, P. A. Thompson, B. Beutler

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Sustained antibody-mediated inhibition of tumor necrosis factor (TNF) activity offers protection against Type I (insulin-dependent) diabetes mellitus in non-obese diabetic (NOD) mice. The mechanism of this effect, however, has remained obscure: TNFα might be required for the development of specific immune responses to islet antigens or it could directly participate in destruction of beta cells. In this study, autoimmune destruction of beta cells was initiated in NOD-severe combined immunodeficient (scid) mice by transfer of NOD Splenic T-cells to induce diabetes. The blockade of TNFα activity was achieved during a narrow window of time after transfer. Transient inhibition of TNFα greatly reduced the number of islet lymphocytes and the incidence of diabetes in recipients of prediabetic NOD spleen cells. Protection extended beyond the interval of effective TNF blockade. Furthermore, the protective effect was only observed if cells were obtained from 6-week-old donors. The suppression of autoimmunity was reversible in the context of adoptive transfer as indicated by the transfer of splenocytes from the primary recipient to a second NOD-scid host led to a diabetic outcome. The blockade of TNFα was accompanied by a considerable increase in spleen size and doubling of the total splenocyte count, suggesting that TNFα might normally eliminate a transplanted T-cell subset within the recipients. Further analysis showed an increase in the absolute count of CD4 + T cells and pronounced distortion of the CD45RB(high) to CD45RB(low) ratio, with a relative augmentation in the CD45RB(low) count in the spleen. TNFα appears to regulate the number and subtype distribution of a transplanted T cell population.

Original languageEnglish (US)
Pages (from-to)1502-1510
Number of pages9
JournalDiabetologia
Volume41
Issue number12
DOIs
StatePublished - Jan 1 1998

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Keywords

  • Autoimmunity
  • Cytokines
  • Immunoregulation
  • TNF
  • Type I diabetes mellitus

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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