Immunomodulatory effects of RXR rexinoids: modulation of high-affinity IL-2R expression enhances susceptibility to denileukin diftitox

Görgün, Güllü; Foss, Francine M.

doi:10.1182/blood-2002-01-0300

Cited by 86 publications

(51 citation statements)

References 28 publications

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“…Although cytokine withdrawal can induce apoptosis and retinoids are known to affect IL-2 production and receptor expression (60,61), addition of IL-2 and IL-4 to cultures in the present studies did not alter the antiapoptotic effects of AGN194204 and 9-cis-retinoic acid. This result was not unexpected because these cytokines do not induce Bcl2a1 expression in naive T lymphocytes, although IL-4 can induce Bcl2 expression (17).…”

Section: Discussionmentioning

confidence: 48%

Retinoid X Receptor Agonists Increase Bcl2a1 Expression and Decrease Apoptosis of Naive T Lymphocytes

Rasooly

Schuster

Gregg

et al. 2005

The Journal of Immunology

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Vitamin A affects many aspects of T lymphocyte development and function. The vitamin A metabolites all-trans- and 9-cis-retinoic acid regulate gene expression by binding to the retinoic acid receptor (RAR), while 9-cis-retinoic acid also binds to the retinoid X receptor (RXR). Naive DO11.10 T lymphocytes expressed mRNA and protein for RAR-α, RXR-α, and RXR-β. DNA microarray analysis was used to identify RXR-responsive genes in naive DO11.10 T lymphocytes treated with the RXR agonist AGN194204. A total of 128 genes was differentially expressed, including 16 (15%) involved in cell growth or apoptosis. Among these was Bcl2a1, an antiapoptotic Bcl2 family member. Quantitative real-time PCR analysis confirmed this finding and demonstrated that Bcl2a1 mRNA expression was significantly greater in nonapoptotic than in apoptotic T lymphocytes. The RXR agonist 9-cis-retinoic acid also increased Bcl2a1 expression, although all-trans-retinoic acid and ligands for other RXR partner receptors did not. Treatment with AGN194204 and 9-cis-retinoic acid significantly decreased apoptosis measured by annexin V staining but did not affect expression of Bcl2 and Bcl-xL. Bcl2a1 promoter activity was examined using a luciferase promoter construct. Both AGN194204 and 9-cis-retinoic acid significantly increased luciferase activity. In summary, these data demonstrate that RXR agonists increase Bcl2a1 promoter activity and increase expression of Bcl2a1 in naive T lymphocytes but do not affect Bcl2 and Bcl-xL expression in naive T lymphocytes. Thus, this effect on Bcl2a1 expression may account for the decreased apoptosis seen in naive T lymphocytes treated with RXR agonists.

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Section: Discussionmentioning

confidence: 48%

Retinoid X Receptor Agonists Increase Bcl2a1 Expression and Decrease Apoptosis of Naive T Lymphocytes

Rasooly

Schuster

Gregg

et al. 2005

The Journal of Immunology

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“…This has been demonstrated in a variety of carcinomas, such as lung, head and neck, ovary and thyroid, and cutaneous lymphomas in people. [39][40][41][42][43][44][45] A recent study showed that retinoid receptor expression is negative in normal canine lymph nodes. In that same study, strong retinoid and rexinoid receptor expression was detected in B-and T-cell canine lymphomas.…”

Section: Discussionmentioning

confidence: 99%

Immunohistochemical Detection of Retinoid Receptors in Tumors from 30 Dogs Diagnosed with Cutaneous Lymphoma

Souza

Valli

Selting

et al. 2010

Journal of Veterinary Internal Medicine

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Background: Retinoids exert their effects by binding to retinoid receptors. Two types of retinoid receptors have been described: retinoic acid receptor (RAR) and retinoid X receptor (RXR), and their subtypes a, b, and g. The expression of subtypes varies depending on the disease process. This study intended to detect the pattern of retinoid receptor expression in cutaneous lymphomas in dogs.Hypothesis: Cutaneous lymphomas in dogs have variable expression of retinoid and retinoid X receptors. Animals: Biopsy specimens from 30 dogs with cutaneous lymphoma. Methods: Tissues of dogs with cutaneous lymphoma were evaluated by immunohistochemistry for expression of retinoid receptors. The tissues were tested for the presence of 3 RAR and RXR subtypes (a, b, and g). Lymphoma immunophenotype was determined by the use of the immunohistochemical markers CD79a (B-cell) and CD3 (T-cell) in all cases.Results: Twenty-nine of 30 dogs were CD3 positive. The retinoid receptors expressed with the greatest frequency were RARb (87% of cases), and RXRa and RXRg (77% of cases). The expression of RARg was not observed.Conclusions and Clinical Relevance: Retinoid and rexinoid receptor binding drugs may have an impact on the treatment of dogs with cutaneous lymphoma.

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“…Bexarotene combined with denileukin diftitox provides a noteworthy example, as bexarotene was shown to increase IL-2Rb (CD122) expression in malignant T cells [232], conferring increased sensitivity to denileukin diftitox, thus forming the rationale for a phase I study combining these two agents [233]. In this study, 14 patients with relapsed/refractory CTCL received bexarotene (75-300 mg daily) with denileukin diftitox (18 mcg/kg daily for 3 days every 21 days).…”

Section: Bexarotenementioning

confidence: 99%

Cutaneous T‐cell lymphoma: 2011 update on diagnosis, risk‐stratification, and management

Wilcox

2011

American J Hematol

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Disease overview: Cutaneous T‐cell lymphomas are a heterogenous group of T‐cell lymphoproliferative disorders involving the skin, the majority of which may be classified as Mycosis fungoides (MF) or Sézary syndrome (SS).Diagnosis: The diagnosis of MF or SS requires the integration of clinical and histopathologic data.Risk‐adapted therapy: Tumor, node, metastasis, and blood (TNMB) staging remains the most important prognostic factor in MF/SS and forms the basis for a “risk‐adapted,” multidisciplinary approach to treatment. For patients with disease limited to the skin, expectant management or skin‐directed therapies is preferred, as both disease‐specific and overall survival for these patients is favorable. In contrast, patients with advanced‐stage disease with significant nodal, visceral, or blood involvement are generally approached with biologic‐response modifiers, denileukin diftitox, and histone deacetylase inhibitors before escalating therapy to include systemic, single‐agent chemotherapy. Multiagent chemotherapy may be used for those patients with extensive visceral involvement requiring rapid disease control. In highly‐selected patients with disease refractory to standard treatments, allogeneic stem‐cell transplantation may be considered. Am. J. Hematol., 2011. © 2011 Wiley‐Liss, Inc.

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Immunomodulatory effects of RXR rexinoids: modulation of high-affinity IL-2R expression enhances susceptibility to denileukin diftitox

Cited by 86 publications

References 28 publications

Retinoid X Receptor Agonists Increase Bcl2a1 Expression and Decrease Apoptosis of Naive T Lymphocytes

Retinoid X Receptor Agonists Increase Bcl2a1 Expression and Decrease Apoptosis of Naive T Lymphocytes

Immunohistochemical Detection of Retinoid Receptors in Tumors from 30 Dogs Diagnosed with Cutaneous Lymphoma

Cutaneous T‐cell lymphoma: 2011 update on diagnosis, risk‐stratification, and management

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