Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma

Marshall, Neil A.; Christie, Lynsey; Munro, Laura; Culligan, Dominic; Johnston, Peter; Barker, Robert N.; Vickers, Mark A.

doi:10.1182/blood-2003-07-2594

Cited by 472 publications

(354 citation statements)

References 33 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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“…Though the expression of CD45RO and CTLA-4/CD152 are also characteristics of CD4 ϩ CD25 ϩ Treg (15), the forkhead/winged helix transcription factor (FoxP3) has been demonstrated to be a unique marker restricted to the Treg (16). CD4 ϩ CD25 ϩ Treg are implicated in a range of disease states including cancer (17)(18)(19)(20), allograft rejection (21,22), allergy (23), autoimmune diseases (24,25), and infectious diseases (26 -28). Emerging evidence support the hypothesis that pathogenesis of persistent virus infections may be directly related to the levels of circulating CD4 ϩ CD25 ϩ Treg or to the balance of the Treg vs effector T cells.…”

Section: H Epatitis B Virus (Hbv)mentioning

confidence: 99%

Circulating and Liver Resident CD4+CD25+ Regulatory T Cells Actively Influence the Antiviral Immune Response and Disease Progression in Patients with Hepatitis B

Jin

et al. 2006

The Journal of Immunology

407

363

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CD4+CD25+ regulatory T cells (Treg) have been shown to maintain immune tolerance against self and foreign Ags, but their role in persistent viral infection has not been well-defined. In this study, we investigated whether and where CD4+CD25+ Treg contribute to the development of chronic hepatitis B (CHB). One hundred twenty-one patients were enrolled, including 16 patients with acute hepatitis B, 76 with CHB, and 29 with chronic severe hepatitis B. We demonstrated that in chronic severe hepatitis B patients, the frequencies of CD4+CD25+ Treg in both PBMC and liver-infiltrating lymphocytes were significantly increased and there was a dramatic increase of FoxP3+-cell and inflammatory cell infiltration in the liver compared with healthy controls. In CHB patients, circulating CD4+CD25+ Treg frequency significantly correlates with serum viral load. In acute hepatitis B patients, circulating CD4+CD25+ Treg frequency was initially low and with time, the profile reversed to exhibit an increased number of circulating Treg in the convalescent phase and restored to normal levels upon resolution. In PBMC taken from infected patients, depletion of CD4+CD25+ Treg led to an increase of IFN-γ production by HBV-Ag-stimulated PBMC. In addition, CD4+CD25+ Treg were capable of suppressing proliferation of autologous PBMC mediated by HBV Ags, which probably reflects the generation of HBV-Ag-specific Treg in circulation and in the liver of HBV-infected patients. Together, our findings suggest that CD4+CD25+ Treg play an active role not only in modulating effectors of immune response to HBV infection, but also in influencing the disease prognosis in patients with hepatitis B.

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“…2,4 As Hodgkin-and Reed-Sternberg cells, the tumor cells in classical Hodgkin lymphoma, usually constitute a small subpopulation of the cells in affected lymph nodes; it is likely that the microenvironment, largely composed of CD4 þ T regulatory 1 cells, has an essential role in the pathophysiology of the disease. 5 As HIV infection usually involves decreased CD4 þ T-cell counts in the peripheral blood, several studies have addressed the issue of the microenvironment in HIV-associated Hodgkin lymphoma and have found the CD4/CD8 T-cell ratio to be inverted. [6][7][8][9] However, the number of cases examined was very small in the majority of the studies 6,8,9 (o10 HIV-positive classical Hodgkin lymphoma cases each).…”

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confidence: 99%

Spindle-shaped CD163+ rosetting macrophages replace CD4+ T-cells in HIV-related classical Hodgkin lymphoma

et al. 2013

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Combination antiretroviral therapy is highly effective in HIV infection, leading to decreased incidences of AIDSdefining neoplasms. However, HIV patients still have a 10-fold increased risk of developing classical Hodgkin lymphoma compared with the general population. As Hodgkin-and Reed-Sternberg cells represent only a minority in the tumor infiltrate, the aim of the present study was to characterize the microenvironment of HIV-related classical Hodgkin lymphoma and compare it with classical Hodgkin lymphoma cases of immunocompetent individuals. The major morphologic differences were the presence of necrotic foci and the absence of epithelioid cell formation in HIV-related Hodgkin lymphoma. We observed a significantly decreased number of CD4 þ T-cells and a significantly increased number of CD163 þ macrophages in HIVrelated Hodgkin lymphoma. Cases exhibiting a 'sarcomatoid' pattern of the reactive infiltrate exhibited significantly greater numbers of macrophages, associating the 'sarcomatoid' pattern to the presence of spindle-shaped macrophages. Whereas, rosetting of CD4 þ T-cells around Hodgkin-and Reed-Sternberg cells was frequently observed in classical Hodgkin lymphoma in immunocompetent persons; rosetting in a subset of HIV-related Hodgkin lymphoma cases appeared to involve cytoplasmic protrusions of spindle-shaped macrophages. HIV-related Hodgkin lymphoma, therefore, is characterized by unique morphologic features, which should be recognized by pathologists.

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Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma

Cited by 472 publications

References 33 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

Circulating and Liver Resident CD4+CD25+ Regulatory T Cells Actively Influence the Antiviral Immune Response and Disease Progression in Patients with Hepatitis B

Spindle-shaped CD163+ rosetting macrophages replace CD4+ T-cells in HIV-related classical Hodgkin lymphoma

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