Enhanced T cell recovery in HIV-1–infected adults through IL-7 treatment

Lévy, Yves; Lacabaratz, Christine; Weiss, Laurence; Viard, Jean‐Paul; Goujard, Cécile; Lelièvre, Jean‐Daniel; Boué, François; Molina, Jean‐Michel; Rouzioux, Christine; Avettand-Fènoël, Véronique; Croughs, Thérèse; Beq, Stéphanie; Thiébaut, Rodolphe; Chêne, Geneviève; Morre, Michel; Delfraissy, Jean‐François

doi:10.1172/jci38052

Cited by 253 publications

(328 citation statements)

References 66 publications

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“…35 The present results extend evidence reported by us in the setting of MA transplantation, 13 but the time when IL-7 levels appeared to be predictive was later after RIC (day þ 30) than after MA regimen (day þ 15), in agreement with the later development of acute GVHD with RIC allo-SCT. 1,2 The present study and other reports 13,17 showing that higher IL-7 levels predate the onset of acute GVHD, and thus, raises a possible limitation of the therapeutic administration of recombinant human IL-7 aiming at improving T-cell reconstitution following lymphopenia 25,32,36 in the case of allo-SCT recipients.…”

Section: Discussionmentioning

confidence: 56%

Plasma levels of IL-7 and IL-15 after reduced intensity conditioned allo-SCT and relationship to acute GVHD

Thiant

Labalette

Trauet

et al. 2010

Bone Marrow Transplant

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To assess the impact of homeostatic expansion on the occurrence of acute GVHD after reduced intensity conditioning (RIC) transplantation, systemic levels of IL-7 and IL-15 and expression of their specific receptor chains were prospectively investigated in 45 fully HLAmatched allograft recipients. IL-7 and IL-15 levels peaked at four-to fivefold over pre-conditioning values. IL-7 levels were inversely correlated to absolute T-cell counts. Peak IL-15 levels positively correlated to concurrent CRP levels, but normalized earlier than IL-7. These results indicate that the kinetic course of IL-7 depends mainly on initiation of T-cell recovery, while IL-15 depends more on peri-transplant inflammation after RIC. Longer duration of the rise in IL-7 levels was associated with preservation of a normal CD4/CD8 ratio. In all, 16 (35%) patients developed grade 2-4 acute GVHD at a median of 42 days post graft, preceded by higher IL-7 levels and more downregulation of IL-7 receptor a chain on CD4 þ T cells than in patients without acute GVHD, suggesting enhanced homeostatic expansion. In multivariate analysis, IL-7 level measured on day þ 30 was the foremost predictive factor for grade 2-4 acute GVHD (P ¼ 0.002). Measurement of IL-7 level after RIC transplantation might help predict risk of subsequent acute GvHD.

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Section: Discussionmentioning

confidence: 56%

Plasma levels of IL-7 and IL-15 after reduced intensity conditioned allo-SCT and relationship to acute GVHD

Thiant

Labalette

Trauet

et al. 2010

Bone Marrow Transplant

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“…In this setting, intermittent IL-7 therapy in HIV and non-HIV conditions also increases CD4 T cells and perturbs significantly T cell homeostasis without any apparent effect on Treg populations, which shows promise. Results of large trials with clinical endpoints are eagerly awaited (34).…”

Section: Discussionmentioning

confidence: 99%

In vivo expansion of naive and activated CD4 ⁺ CD25 ⁺ FOXP3 ⁺ regulatory T cell populations in interleukin-2–treated HIV patients

Weiss

Letimier

Carrière

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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HIV-1 infection is characterized by a progressive decline in CD4 + T cells leading to a state of profound immunodeficiency. IL-2 therapy has been shown to improve CD4 + counts beyond that observed with antiretroviral therapy. Recent phase III trials revealed that despite a sustained increase in CD4 + counts, IL-2-treated patients did not experience a better clinical outcome [Abrams D, et al. (2009) N Engl J Med 361(16):1548-1559. To explain these disappointing results, we have studied phenotypic, functional, and molecular characteristics of CD4 + T cell populations in IL-2-treated patients. We found that the principal effect of long-term IL-2 therapy was the expansion of two distinct CD4 + CD25 + T cell populations (CD4 + CD25 lo CD127 lo FOXP3 + and CD4 + CD25 hi CD127 lo FOXP3 hi ) that shared phenotypic markers of Treg but could be distinguished by the levels of CD25 and FOXP3 expression. IL-2-expanded CD4 + CD25 + T cells suppressed proliferation of effector cells in vitro and had gene expression profiles similar to those of natural regulatory CD4 + CD25 hi FOXP3 + T cells (Treg) from healthy donors, an immunosuppressive T cell subset critically important for the maintenance of self-tolerance. We propose that the sustained increase of the peripheral Treg pool in IL-2-treated HIV patients may account for the unexpected clinical observation that patients with the greatest expansion of CD4 + T cells had a higher relative risk of clinical progression to AIDS. molecular profiling | immune-based therapy H IV infection is mainly associated with a progressive decrease in the number of CD4 + T lymphocytes and defective CD4-and CD8-specific T cell responses against HIV and other pathogens. Quantitative and qualitative CD4 T cell reconstitution following introduction of antiretroviral therapy (ART) in HIVinfected patients is often incomplete, leading one to evaluate the impact of immune-based therapy in combination with ART. In the past 20 years, a large set of clinical trials demonstrated that intermittent interleukin (IL)-2 therapy increased the CD4 T cell pool in HIV-infected patients and induced, in a large majority of patients, significant and sustained increases in CD4 T cell count beyond that seen in patients treated with antiviral drugs alone. In particular, recombinant IL-2 therapy raised naive and central memory CD4 + cells expressing CD25, the α-chain of the IL-2 receptor, more than antiretroviral drugs alone (1-6). This population accounted for up to 70% of the total CD4 + T cell pool of IL-2-treated patients and persisted for a long time.The clinical impact of IL-2 was evaluated in two long-run large phase III trials (SILCAAT and ESPRIT) involving almost 6,000 chronically HIV-1-infected patients. Results recently reported showed that, despite a sustained increase in CD4 + T cell counts, over a median follow-up of 7-8 years, IL-2-treated patients did not experience a better clinical outcome (7). These disappointing results have remained unexplained so far.In mice, IL-2 has been shown to be essential for the...

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“…Accordingly, IL-2 therapy in lymphopenic patients leads to increases in regulatory-like CD4 T cell counts at the expense of the conventional T cell compartment, leading to altered responses to pathogens (46)(47)(48). Conversely, administration of IL-7 in humans induces expansion of naive and memory T cell subsets (49)(50)(51) and, in some clinical trials, a relative decrease in the percentage of regulatory CD4 + T cells was observed (52). Thus, on one hand, the capacity of IL-7 to augment conventional T cell proliferation with minimal concomitant regulatory T cell expansion may be clinically exploitable in the treatment of patients with lymphopenia, especially in the case of chronic viral diseases (53) or cancer immunotherapy (54).…”

Section: Regulatory Cd4 + T Cells Receive Help From Conventional Cd4 mentioning

confidence: 99%

IL-2 and IL-7 Determine the Homeostatic Balance between the Regulatory and Conventional CD4+ T Cell Compartments during Peripheral T Cell Reconstitution

Campion

Pommier²,

Delpoux³

et al. 2012

The Journal of Immunology

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Work over the last decades has led to the identification of the factors that influence the survival and homeostasis of conventional T cells. IL-7 and TCR signaling promote the survival of naive CD4+ and CD8+ T cells in lymphoreplete mice and their proliferation in a lymphopenic environment, whereas survival and homeostatic proliferation of memory CD4+ and CD8+ T cells crucially depend on a combination of IL-7 and IL-15. In contrast, there is little information regarding the factors driving the proliferation of regulatory CD4+ T cells in response to lymphopenia. In this study, we investigated whether regulatory CD4+ T cell proliferation in response to lymphopenia was guided by classical homeostatic resources, such as IL-2, IL-7, or TCR–MHC interactions. Altogether, our data suggest that, although homeostatic proliferation of conventional naive CD4+ T cells is closely related to IL-7 levels, the proliferation of regulatory CD4+ T cells in response to lymphopenia appears to be primarily controlled by IL-2. The capacity of IL-7 to augment conventional T cell proliferation with minimal concomitant regulatory T cell expansion may be clinically exploitable in the treatment of patients with lymphopenia, especially in the case of chronic viral diseases or cancer immunotherapy.

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Enhanced T cell recovery in HIV-1–infected adults through IL-7 treatment

Abstract: HIV infection results in CD4

Cited by 253 publications

References 66 publications

Plasma levels of IL-7 and IL-15 after reduced intensity conditioned allo-SCT and relationship to acute GVHD

Plasma levels of IL-7 and IL-15 after reduced intensity conditioned allo-SCT and relationship to acute GVHD

In vivo expansion of naive and activated CD4 ⁺ CD25 ⁺ FOXP3 ⁺ regulatory T cell populations in interleukin-2–treated HIV patients

IL-2 and IL-7 Determine the Homeostatic Balance between the Regulatory and Conventional CD4+ T Cell Compartments during Peripheral T Cell Reconstitution

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Enhanced T cell recovery in HIV-1–infected adults through IL-7 treatment

Abstract: HIV infection results in CD4

Cited by 253 publications

References 66 publications

Plasma levels of IL-7 and IL-15 after reduced intensity conditioned allo-SCT and relationship to acute GVHD

Plasma levels of IL-7 and IL-15 after reduced intensity conditioned allo-SCT and relationship to acute GVHD

In vivo expansion of naive and activated CD4 + CD25 + FOXP3 + regulatory T cell populations in interleukin-2–treated HIV patients

IL-2 and IL-7 Determine the Homeostatic Balance between the Regulatory and Conventional CD4+ T Cell Compartments during Peripheral T Cell Reconstitution

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In vivo expansion of naive and activated CD4 ⁺ CD25 ⁺ FOXP3 ⁺ regulatory T cell populations in interleukin-2–treated HIV patients