The role of interleukin-3 in classical Hodgkin's disease

Aldinucci, Donatella; Olivo, Karin; Lorenzon, Debora; Poletto, Dalisa; Gloghini, Annunziata; Carbone, Antonino; Pinto, Antonio

doi:10.1080/10428190400013712

Cited by 36 publications

(37 citation statements)

References 95 publications

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“…Because pDC are found to infiltrate a series of tumors, they are thought to play an important role for cancer immunity (2). Although the expression of GrB in tumor-infiltrating pDC has not been investigated so far, the main cytokines responsible for the induction of GrB in pDC, namely IL-3 and IL-10 (6), can be detected in the environment of neoplastic diseases (53,54). This suggests that GrB-secreting pDC in such an environment may be involved in suppressing the expansion of tumor-specific T cells, thereby contributing to a potential tumor evasion.…”

Section: Discussionmentioning

confidence: 99%

Antiviral Vaccines License T Cell Responses by Suppressing Granzyme B Levels in Human Plasmacytoid Dendritic Cells

Fabricius

Nußbaum

Busch

et al. 2013

The Journal of Immunology

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Human plasmacytoid dendritic cells (pDC) are important modulators of adaptive T cell responses during viral infections. Recently, we found that human pDC produce the serine protease granzyme B (GrB), thereby regulating T cell proliferation in a GrB-dependent manner. In this study, we demonstrate that intrinsic GrB production by pDC is significantly inhibited in vitro and in vivo by clinically used vaccines against viral infections such as tick-borne encephalitis. We show that pDC GrB levels inversely correlate with the proliferative response of coincubated T cells and that GrB suppression by a specific Ab or a GrB substrate inhibitor results in enhanced T cell proliferation, suggesting a predominant role of GrB in pDC-dependent T cell licensing. Functionally, we demonstrate that GrBhigh but not GrBlow pDC transfer GrB to T cells and may degrade the ζ-chain of the TCR in a GrB-dependent fashion, thereby providing a possible explanation for the observed T cell suppression by GrB-expressing pDC. Modulation of pDC-derived GrB activity represents a previously unknown mechanism by which both antiviral and vaccine-induced T cell responses may be regulated in vivo. Our results provide novel insights into pDC biology during vaccinations and may contribute to an improvement of prophylactic and therapeutic vaccines.

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Section: Discussionmentioning

confidence: 99%

Antiviral Vaccines License T Cell Responses by Suppressing Granzyme B Levels in Human Plasmacytoid Dendritic Cells

Fabricius

Nußbaum

Busch

et al. 2013

The Journal of Immunology

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“…55 Increased expression of CD123/IL3Ra has subsequently been demonstrated in related malignancies, including MDS, chronic myeloid leukemia, and aggressive NHLs, among others. [56][57][58] The a subunit of IL-3R is a type I transmembrane glycoprotein (cytokine receptor superfamily) that co-dimers with CD131 (common b chain). Leukemic blasts seem to differentially express IL-3Ra compared with normal stem cells, 55 and this may relate to differential sensitivity to therapy.…”

Section: Novel Therapymentioning

confidence: 99%

Treatment of blastic plasmacytoid dendritic cell neoplasm

Sullivan

Rizzieri

2016

Hematology

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Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare myeloid malignancy with no defined standard of care. BPDCN presents most commonly with skin lesions with or without extramedullary organ involvement before leukemic dissemination. As a result of its clinical ambiguity, differentiating BPDCN from benign skin lesions or those of acute myeloid leukemia with leukemia cutis is challenging. BPDCN is most easily defined by the phenotype CD4 1 CD56 1 CD1231 lineage -MPO -, although many patients will present with variable expression of CD4, CD56, or alternate plasmacytoid markers, which compounds the difficulty in differentiating BPDCN from other myeloid or lymphoid malignancies. Chromosomal aberrations are frequent, and the mutational landscape of BPDCN is being rapidly characterized although no obvious molecular target for chemoimmunotherapy has been identified. Chemotherapy regimens developed for acute myeloid leukemia, acute lymphoid leukemia, and myelodysplastic syndrome have all been used to treat BPDCN. Relapse is frequent, and overall survival is quite poor. Allogeneic transplantation offers a chance at prolonged remission and possible cure for those who are eligible; unfortunately, relapse remains high ranging from 30% to 40%. Novel therapies such as SL-401, a diphtheria toxin conjugated to interleukin-3 (IL-3) is commonly overexpressed in BPDCN and other aggressive myeloid malignancies and has shown considerable promise in ongoing clinical trials. Future work with SL-401 will define its place in treating relapsed or refractory disease as well as its role as a first-line therapy or bridge to transplantation. Learning Objectives• To understand the clinical and laboratory approach for differentiating BPDCN from acute myeloid leukemia with cutaneous manifestations • To consider appropriate first-line and salvage treatments for BPDCN, including the utility of hematopoietic allogeneic stem cell transplantation and novel agents in various patient populations

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“…Cytokines and lymphokines from CD4 + T cells can also activate CD8 + CTL, NK cells and macrophages, which have all been shown to be involved in tumor immunity (Adam et al, 2003;Gonthier et al, 2004;Ikeda et al, 2002;Peipp & Valerius, 2002;Smyth et al, 2002). Immunoregulatory cytokines such as IL-10 and TGF- play an important role in immune tolerance, and it seems that suppressor effect of regulatory T cells (CD4 + CD25 + ) on the development of tumor associated antigen-reactive lymphocytes is independent of cytokines (Aldinucci et al, 2005). Contributing to the complexity of the interactions between the reactive background and malignant cells, immune cells present in the local infiltrate have proved capable of modulating apoptosis and of inducing proliferation of tumoral cells via death receptors, cytotoxic granule liberation, and withdrawal of growth factors or production of immunosuppressive cytokines (Atkinson & Bleackley, 1995;Berke, 1995;de Visser & Kast, 1999;.…”

Section: Antitumoral Immunitymentioning

confidence: 99%

“…It has been estimated that EBV-specific T-cells might constitute up to 5% of circulating CD8 + T-cells (Hislop et al, 2002;Rickinson & Kieff, 2001 (Hsu et al, 1989) and IL-3 have demonstrated to present significant biological activity as growth and antiapoptotic factor for H/RS cells (Aldinucci et al, 2005). Serum levels of the receptor antagonist IL-1 (IL-1r ) are elevated in HL patients, patients with B symptoms have significantly lower levels of IL-1r than those without symptoms (Gruss et al, 1992).…”

Section: Role Of Virus In Hlmentioning

confidence: 99%