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Arlene Sharpe

Publications and source records attributed to Arlene Sharpe.

7 recordsLinked to original sources
PubMed2006

CD48 controls T-cell and antigen-presenting cell functions in experimental colitis.

BACKGROUND & AIMS: The cell-surface receptor CD48 is a lipid-anchored protein expressed on all antigen-presenting cells and T cells. CD2 and 2B4 are known ligands for CD48, which themselves are expressed on the surface of hematopoietic cells. Here we examine the effect of CD48 in the development of chronic experimental colitis and how CD48 affects adaptive and innate immune functions. METHODS: The role of CD48 in experimental colitis was first assessed by transferring CD4(+)CD45RB(hi) cells isolated from either wild-type or CD48(-/-) mice into either Rag-2(-/-) or CD48(-/-) x Rag-2(-/-) mice. Development of chronic colitis in these adoptively transferred mice was assessed by disease activity index, histology, and production of interferon-gamma in mesenteric lymph nodes. Relevant functions of CD48(-/-)CD4(+) T cells and CD48(-/-) macrophages were examined using in vitro assays. In a second set of experiments, the efficacy of anti-CD48 in prevention or treatment of chronic colitis was determined. RESULTS: CD48(-/-)CD4(+) cells induced colitis when transferred into Rag-2(-/-) mice, but not when introduced into CD48(-/-) x Rag-2(-/-) recipients. However, both recipient mouse strains developed colitis upon adoptive transfer of wild-type CD4(+) cells. Consistent with a CD4(+) T-cell defect was the observation that in vitro proliferation of CD48(-/-)CD4(+) T cells was impaired upon stimulation with CD48(-/-) macrophages. In vitro evidence for a modest macrophage functional defect was apparent because CD48(-/-) macrophages produced less tumor necrosis factor alpha and interleukin 12 than wild-type cells upon stimulation with lipopolysaccharide. Peritoneal macrophages also showed a defect in clearance of gram-negative bacteria in vitro. Treatment of the CD4(+)CD45RB(hi)-->Rag-2(-/-) mice or the wild-type BM-->tg26 mice with anti-CD48 (HM48-1) ameliorated development of colitis, even after its induction. CONCLUSIONS: Both CD48-dependent activation of macrophages and CD48-controlled activation of T cells contribute to maintaining the inflammatory response. Consequently, T cell-induced experimental colitis is ameliorated only when CD48 is absent from both T cells and antigen-presenting cells. Because anti-CD48 interferes with these processes, anti-human CD48 antibody treatment may represent a novel therapy for inflammatory bowel disease patients.

Animals↗
PubMed2006

Synergistic costimulation by both B7 molecules regulates colitis pathogenesis.

It has been reported that B7-1 and B7-2 play different roles in the pathogenesis of autoimmunity, but this issue is controversial. Here we analyzed colitis induced by transfer of CD45RB(high) CD4+ T cells to immune-deficient recipients that lack expression of either B7-1 or B7-2. Surprisingly, disease was greatly accelerated in Rag(-/-) recipients deficient for either B7 molecule. Antigen presenting cells (APCs) lacking B7-1 or B7-2 stimulated T cell proliferation in vitro, but caused suboptimal IL-2 production, leading to decreased induction of CTLA-4. The data suggest that regulatory T cells function relatively normally in B7 single-deficient recipients, but they cannot restrain the increased pathogenesis by naïve cells primed in B7 single-deficient mice. Therefore, the inhibitory effect of CTLA-4 on pathogenic T cells likely slows colitis, even in the absence of regulatory T cells. While a full block of costimulation may prevent autoimmunity, our data indicate, surprisingly, that a partial block may in some cases augment disease.

Antigens, CD↗
PubMed2005

Epstein-Barr virus nuclear antigen 1 does not induce lymphoma in transgenic FVB mice.

The lymphoma-inducing potential of Ig heavy-chain enhancer- and promoter-regulated Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) was evaluated in three transgenic FVB mouse lineages. EBNA1 was expressed at a higher level in transgenic B220(+) splenocytes than in EBV-infected lymphoblastoid cell lines. EBNA1 was also expressed in B220(-) transgenic splenocytes and thymocytes. Before killing and assessments at 18-26 months, EBNA1-transgenic mice did not differ from control mice in mortality. At 18-26 months EBNA1-transgenic mice did not differ from littermate control in ultimate body weight, in spleen size or weight, in lymph node, kidney, liver, or spleen histology, in splenocyte fractions positive for cluster of differentiation (CD)3epsilon, CD4, CD8, CD62L, B220, CD5, IgM, IgD, MHC class II, CD11b, or CD25, or in serum IgM, IgG, or total Ig levels. Lymphomas were not found in spleens or other organs of 18- to 26-month-old EBNA1-transgenic (n=86) or control (n=45) FVB mice. EBNA1-transgenic lineages had a higher pulmonary adenoma prevalence than did littermate controls (39% versus 7%). However, the adenoma prevalence was not higher in EBNA1-transgenic mice than has been described for FVB mice, and EBNA1 was not expressed in normal pulmonary epithelia or adenomas.

Adenomatosis, Pulmonary↗
PubMed2003

Paradoxical dampening of anti-islet self-reactivity but promotion of diabetes by OX40 ligand.

Costimulatory signals received by diabetogenic T cells during priming by or upon secondary encounter with autoantigen are decisive in determining the outcome of autoimmune attack. The OX40-OX40 ligand (OX40L) costimulatory pathway is known to influence T cell responses, prompting us to examine its role in autoimmune diabetes. A null allele at OX40L completely prevented diabetes development in nonobese diabetic mice and strongly reduced its incidence in a TCR transgenic model (BDC2.5). However, somewhat paradoxically, the initial activation of T cells responsive to islet beta cell Ag was slightly faster and more efficient in the absence of OX40L, with an increased degree of cell proliferation and survival in the deficient hosts. Activated T cell migration into and retention within the islets was also slightly accelerated. When challenged in vitro, splenocytes from BDC2.5.OX40L(o/o) mice showed no altered reactivity to exogenously added peptide, no bias to the Th1 or Th2 phenotype, and no alteration in T cell survival. Thus, the OX40/OX40L axis has the paradoxical effect of dampening the early activation and migration of autoimmune T cells, but sustains the long-term progression to autoimmune destruction.

Adoptive Transfer↗
PubMed2003

Cutting edge: transplantation tolerance through enhanced CTLA-4 expression.

Knockout and blocking studies have shown a critical role for CTLA-4 in peripheral tolerance, however, it is unknown whether augmenting CTLA-4 expression actually promotes tolerance. Here we demonstrate a specific and requisite role for CTLA-4 and its up-regulation in tolerance through anti-CD45RB. First, long-term murine islet allograft survival induced by anti-CD45RB is prevented by CTLA4-Ig, which interferes with B7:CTLA-4 interactions. Second, anti-CD45RB is ineffective in recipients lacking CTLA-4, B7-1, and B7-2. In contrast, CTLA4-Ig, which targets B7 on allogeneic cells, promotes long-term engraftment in these mice. Moreover, anti-CD45RB was effective in B7-deficient controls expressing CTLA-4. Finally, in wild-type mice, CTLA-4 expression returned to baseline 17 days after receiving anti-CD45RB, and was refractory to further increase. Transplantation and anti-CD45RB therapy at this time could neither augment CTLA-4 nor prolong engraftment. These data demonstrate a specific role for CTLA-4 in anti-CD45RB-mediated tolerance and indicate that CTLA-4 up-regulation can directly promote allograft survival.

Abatacept↗
PubMed2002

Role of B7 costimulatory molecules in the adjuvant activity of the heat-labile enterotoxin of Escherichia coli.

Much interest has been directed at understanding the adjuvant properties of the heat-labile enterotoxin of Escherichia coli (LT). In this study, we have assessed how LT compared with the nonenzymatic mutant LT (E112K) affect the level of B7-1 and B7-2 expression on APCs, and we determined how these costimulatory molecules influence their adjuvant properties. Analysis of B7-1 and B7-2 expression on B cells revealed that LT enhanced B7-2 but not B7-1, while LT (E112K) had no effect on the expression of either costimulatory molecule. Treatment of macrophage or dendritic cells with LT resulted in a predominant enhancement of B7-2, while LT (E112K) induced mainly B7-1 expression. Analysis of LT- and LT (E112K)-treated B cells, macrophage, and dendritic cells also revealed significant differences in their ability to enhance anti-CD3-stimulated CD4(+) T cell proliferative responses via B7-1 and B7-2. Furthermore, the ability of LT to enhance both Ab and CD4(+) T cell responses to a coadministered Ag was severely abrogated in B7-2- but not B7-1-deficient mice. In contrast, the in vivo adjuvant properties of LT (E112K) appeared to be mediated by both B7-1 and B7-2 for optimal CD4(+) T cell responses, while B7-1 appeared to be the predominant B7 molecule involved in the ability of LT (E112K) to augment Ab responses to a coadministered Ag. These findings demonstrate distinct differences in the ability of LT and LT (E112K) to enhance B7-1 and B7-2 on APC, as well as a dependence upon these costimulatory molecules for their adjuvant properties.

Adjuvants, Immunologic↗