Immunoregulatory T Cells in the Peripheral Blood of Patients with Hodgkin’s Lymphoma

Baráth, Sándor; Aleksza, Magdolna; Keresztes, Katalin; Tóth, Judit; Sipka, Sándor; Szegedi, Gyula; Illés, Árpád

doi:10.1159/000094678

Cited by 30 publications

(25 citation statements)

References 23 publications

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“…Changes within individuals have not been evaluated to corroborate the shift reported from a low CD4/CD8 ratio to total lymphocytopenia during the 1-2 years before HL diagnosis. 8 HL in the general population that is unrelated to HIV is associated with elevated circulating levels of immunoregulatory T cells, [24][25][26] as well as with T-cell and total lymphopenia, 27 perhaps the result of chemoattraction of T cells from the blood to tumorassociated malignant Hodgkin/Reed-Sternberg cells. [28][29][30] Chemokines CCL22 and especially CCL17 have been specifically implicated, 28,29,31 but other chemokines may also be involved.…”

Section: Discussionmentioning

confidence: 99%

HIV-associated Hodgkin lymphoma during the first months on combination antiretroviral therapy

Lanoy

Rosenberg

Fily

et al. 2011

Blood

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Hodgkin lymphoma (HL) incidence with HIV infection may have increased with the introduction of combination antiretroviral therapy (cART), suggesting that immune reconstitution may contribute to some cases. We evaluated HL risk with cART during the first months of treatment. With 187 HL cases among 64 368 HIV patients in France, relative rates (RRs) and 95% confidence intervals (CIs) of HL were estimated using Poisson models for duration of cART, CD4 count, and HIV load, with and without adjustment for demographic/ clinical covariates. HL risk was unrelated to cART use overall, but it was related to time intervals after cART initiation (P ‫؍‬ .006). Risk was especially and significantly elevated in months 1-3 on cART (RR 2.95, CI 1.64-5.31), lower in months 4-6 (RR 1.63), and null with longer use (RR 1.00). CD4 count was strongly associated with HL risk (P < 10 ؊6 ), with the highest HL incidence at 50-99 CD4 cells/mm 3 . With adjustment for CD4 count and covariates, HL risk was elevated, but not significantly (RR 1.42), in months 1-3 on cART. HIV load had no added effect. HL risk increased significantly soon after cART initiation, which was largely explained by the CD4 count. IntroductionHodgkin lymphoma (HL) incidence is significantly elevated in the HIV-infected population. [1][2][3] In addition, since the advent of combination antiretroviral therapy (cART) in 1996, studies in the United States 4 and the United Kingdom 5 have reported an increase in the incidence of HL compared with the pre-cART era. For example, among people with AIDS in the United States, the incidence of HL was shown to be elevated 8-fold compared with the general population during the pre-cART era, and this increased significantly to 13-fold during the cART era. 1 Excess risk of HL in a second US population and among the HIV-infected population in France was shown to be very high during the pre-cART era. 2,6 In the French study, HL incidence increased even more (by 1.4-fold) during the cART era compared with the pre-cART era. 2 In the Swiss HIV Cohort Study, HL risk was 3-fold higher in the cART era compared with the pre-cART era in an analysis of the first 18 cases, 7 but this was not statistically significant and no increment in the cART era was found in an updated analysis of 47 HL cases. 8 Increased HL in the cART era has been postulated to be related to the actual use of cART, with a potential role for immunologic mechanisms. 2,4,9 Some support for an effect of cART on HL risk was provided by the British and initial Swiss studies, but these findings were marginally significant and were adjusted little or not at all for immune deficiency. 5,7 The British study also suggested that the excess risk of HL might specifically relate to the use of non-nucleoside reverse transcriptase inhibitors (NNRTIs). 5 Immune perturbation, and its control by cART, is likely to be integral to the development of HIV-associated HL. The relative risk (RR) of HIV-associated HL is 3.5-fold higher after AIDS onset, 10 and a lower CD4 lymphocyte count generally ...

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Section: Discussionmentioning

confidence: 99%

HIV-associated Hodgkin lymphoma during the first months on combination antiretroviral therapy

Lanoy

Rosenberg

Fily

et al. 2011

Blood

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“…In view of the previous demonstration that IL-10-expressing Tr1 CD4 ϩ T cells were overexpressed in Hodgkin disease, 20,36 we enumerated Tr1 cells both in peripheral blood and involved tissue samples and again compared with healthy controls. Median percentage of IL-10 plus Tr1 cells of CD4 T cells in patients' PBMCs (n ϭ 20) versus healthy controls' PBMCs (n ϭ 12), was 14.0% versus 7.1%, respectively (P ϭ .144, rank sum test; Figure S2).…”

Section: Enumeration Of Treg Cells In Patients' Pbmcs and Involved Timentioning

confidence: 99%

Local and systemic induction of CD4+CD25+ regulatory T-cell population by non-Hodgkin lymphoma

Mittal

Marshall

Duncan

et al. 2008

Blood

109

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IntroductionB-cell non-Hodgkin lymphoma (NHL) is a heterogeneous group of lymphoid malignancies, many of which remain incurable. Increasing evidence suggests that the tumor microenvironment plays an important role, in determining not only the severity of disease, but also response to therapy. [1][2][3][4] Ansell et al 4 demonstrated that higher numbers of activated CD4 ϩ cells among the tumor-infiltrating lymphocytes of diffuse large B-cell NHL were associated with a better prognosis. More recently, analyses of gene expression using microchips in follicular and diffuse large B-cell lymphomas have indicated that the nature of nonmalignant lymphocytes is important prognostically. 5,6 It is becoming clear that a critical component of the immune response to malignancies includes regulatory T (Treg) cells. 7 There are at least 2 forms of Treg cells, "natural" and "induced." The former suppress, at least in vitro, via undefined mechanisms dependent on cell-cell contact; the latter inhibit primarily through the secretion of immunosuppressive cytokines such as IL-10. 8 Natural Treg cells constitutively express high levels of CD25 and are believed to arise as a suppressive population in Hassall corpuscles within the thymus, 9 but there is evidence that they may also arise peripherally. 10 There have been difficulties in identifying unique markers for the natural population. 7 Expression of the forkhead/winged helix transcription factor (FoxP3) The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on May 10, 2018. by guest www.bloodjournal.org FromWe therefore enumerated Treg cells in peripheral blood and involved tissue samples from NHL patients and determined whether the tumor cells induce their differentiation. Methods PatientsBetween January 2006 and February 2007, 30 newly diagnosed patients with B-cell NHL (age range: 17 to 93 years, mean ϭ 62, SD ϭ 22) were recruited from Aberdeen Royal Infirmary, United Kingdom, which is the sole specialty hospital serving the Grampian area. The study received approval from The Grampian NHS local ethics committee, Aberdeen, and informed consent was obtained from all patients in accordance with the Declaration of Helsinki. An age-matched control group comprised 13 healthy individuals (age range: 20 to 90 years, mean ϭ 58, SD ϭ 17) admitted for minor surgical procedures and 2 individuals with benign lymphadenopathy. Patient characteristics are described in Table 1. All initial samples were obtained before any antilymphoma treatment was given. ReagentsThe control recall antigens, mycobacterial PPD (Statens Seruminstitut, Copenhagen, Denmark), diphtheria, poliomyelitis, and tetanus (DPT) vaccine (Aventis Pasteur, Strasbourg, France), T-cell mitogen concanavalin A (ConA; SigmaAldrich, Amersham, United Kingdom), and anti-CD3/28 Dynabeads (Dyn...

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“…6,7 Tregs are elevated in the peripheral blood of HL patients compared to healthy controls, and in those patients with active disease compared to those in remission. 8,9 Their numbers are also increased in HL tumor tissues where they are found close to HRS cells. 9 -11 In HL, an increased number of Tregs is associated with the loss of LMP1-and LMP2-specific immunity, whereas depletion of Tregs from peripheral blood mononuclear cells (PBMCs) enhances EBV-specific immunity.…”

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confidence: 97%

Expression of the Epstein-Barr Virus-Encoded Epstein-Barr Virus Nuclear Antigen 1 in Hodgkin's Lymphoma Cells Mediates Up-Regulation of CCL20 and the Migration of Regulatory T Cells

Baumforth

Birgersdotter

Reynolds

et al. 2008

The American Journal of Pathology

168

136

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The Epstein-Barr virus (EBV) is associated with the development of several human tumors, including Hodgkin's lymphoma (HL) and EBV-positive undifferentiated nasopharyngeal carcinoma (NPC).1 In HL, the malignant Hodgkin's and Reed-Sternberg (HRS) cells constitute only a minority of the total tumor mass, and are surrounded by variable proportions of nonmalignant reactive cells. In approximately onehalf of HL, EBV can be detected in HRS cells, where the virus expresses a limited subset of genes; these include the Epstein-Barr nuclear antigen-1 (EBNA1) and the latent membrane proteins, LMP1 and LMP2.2 Although EBV-specific cytotoxic T cells (CTLs) can be detected in HL and NPC and have been shown to kill LMP1-and LMP2-expressing cells in vitro, they are unable to eliminate EBV-infected tumor cells in vivo. [3][4][5] This failure may be because of increased recruitment of regulatory T cells

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Immunoregulatory T Cells in the Peripheral Blood of Patients with Hodgkin’s Lymphoma

Cited by 30 publications

References 23 publications

HIV-associated Hodgkin lymphoma during the first months on combination antiretroviral therapy

HIV-associated Hodgkin lymphoma during the first months on combination antiretroviral therapy

Local and systemic induction of CD4+CD25+ regulatory T-cell population by non-Hodgkin lymphoma

Expression of the Epstein-Barr Virus-Encoded Epstein-Barr Virus Nuclear Antigen 1 in Hodgkin's Lymphoma Cells Mediates Up-Regulation of CCL20 and the Migration of Regulatory T Cells

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