New therapy to revert dysfunctional antibody responses during HIV-1 infection

Chiodi, Francesca

doi:10.1172/jci44872

Cited by 8 publications

(8 citation statements)

References 17 publications

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“…Immunofluorescent studies indicate that PD-1 and PD-L1 are expressed on different populations of cardiac cells. Thus, while both paracrine and autocrine modes of actions are proposed for regulation of immune cells by the PD-1/PD-L1 pathway [ 34 , 35 ], our findings suggest primarily a paracrine mode of action for this pathway in the ischemic-reperfused heart.…”

Section: Discussionmentioning

confidence: 66%

Upregulation of Programmed Death-1 and Its Ligand in Cardiac Injury Models: Interaction with GADD153

Baban

Liu

et al. 2015

PLoS ONE

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PurposeProgrammed Death-1 (PD-1) and its ligand, PD-L1, are regulators of immune/ inflammatory mechanisms. We explored the potential involvement of PD-1/PD-L1 pathway in the inflammatory response and tissue damage in cardiac injury models.Experimental DesignIschemic-reperfused and cryoinjured hearts were processed for flow cytometry and immunohistochemical studies for determination of cardiac PD-1 and PD-L1 in the context of assessment of the growth arrest- and DNA damage-inducible protein 153 (GADD153) which regulates both inflammation and cell death. Further, we explored the potential ability of injured cardiac cells to influence proliferation of T lymphocytes.ResultsThe isolated ischemic-reperfused hearts displayed marked increases in expression of PD-1 and PD-L1 in cardiomyocytes; however, immunofluorescent studies indicate that PD-1 and PD-L1 are not primarily co-expressed on the same cardiomyocytes. Upregulation of PD-1/PD-L1 was associated with a) marked increases in GADD153 and interleukin (IL)-17 but a mild increase in IL-10 and b) disruption of mitochondrial membrane potential (ψm) as well as apoptotic and necrotic cell death. Importantly, while isotype matching treatment did not affect the aforementioned changes, treatment with the PD-L1 blocking antibody reversed those effects in association with marked cardioprotection. Further, ischemic-reperfused cardiac cells reduced proliferation of T lymphocytes, an effect partially reversed by PD-L1 antibody. Subsequent studies using the cryoinjury model of myocardial infarction revealed significant increases in PD-1, PD-L1, GADD153 and IL-17 positive cells in association with significant apoptosis/necrosis.ConclusionsThe data suggest that upregulation of PD-1/PD-L1 pathway in cardiac injury models mediates tissue damage likely through a paracrine mechanism. Importantly, inhibition of T cell proliferation by ischemic-reperfused cardiac cells is consistent with the negative immunoregulatory role of PD-1/PD-L1 pathway, likely reflecting an endogenous cardiac mechanism to curtail the deleterious impact of infiltrating immune cells to the damaged myocardium. The balance of these countervailing effects determines the extent of cardiac injury.

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Section: Discussionmentioning

confidence: 66%

Upregulation of Programmed Death-1 and Its Ligand in Cardiac Injury Models: Interaction with GADD153

Baban

Liu

et al. 2015

PLoS ONE

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“…Understanding the mechanisms leading to loss of memory B cells and serological memory during HIV‐1 infection could potentially lead to new approaches for therapy and/or vaccination [40]. Microbial translocation, which occurs through the damaged gut epithelium, and the associated immune activation have been shown to play a major role in HIV‐1 pathogenesis [13].…”

Section: Discussionmentioning

confidence: 99%

Immune activation and increased IL‐21R expression are associated with the loss of memory B cells during HIV‐1 infection

Ruffin

Lantto

Pensieroso

et al. 2012

Journal of Internal Medicine

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Abstract. Ruffin N, Lantto R, Pensieroso S, Sammicheli S, Hejdeman B, Rethi B, Chiodi F (Karolinska Institutet, Stockholm; and South Hospital, Stockholm, Sweden). Immune activation and increased IL-21R expression are associated with the loss of memory B cells during HIV-1 infection. J Intern Med 2012; 272: 492-503.Objectives. Microbial translocation and chronic immune activation were previously shown to be associated with impairment of T cell functions and disease progression during infection with human immunodeficiency virus type-1 (HIV-1); however, their impact on B cell function and number remains unknown. By measuring markers of immune activation and molecules involved in apoptosis regulation, we have evaluated the association between microbial translocation and loss of memory B cells in HIV-1-infected patients.Methods. Markers of activation [the interleukin-21 receptor (IL-21R) and CD38] and apoptosis (Bim, Bcl-2 and annexin V) were measured in B cell subpopulations by multicolour flow cytometry. Levels of soluble CD14 (sCD14) and lipopolysaccharide (LPS), measures of microbial translocation, were determined in plasma. Purified B cells were also exposed in vitro to Toll-like receptor (TLR) ligands.

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“…In this regard, the treatment of SIV-infected macaques with PD-1-specific blocking antibodies had a measurable effect on humoral immunity by enhancing the survival of memory B cells and the production of SIV-specific antibodies. The approach with PD-1 blocking antibodies became a successful therapeutic strategy, although the molecular scenario targeted by this therapy needs further clarification [48]. It is important to know the cellular source, either paracrine or autocrine, of the PD-1 ligands (PD-L1 and PD-L2).…”

Section: Redistribution Of Classic and Rare Populations Of Memory B Cmentioning

confidence: 99%

Impairment of B-cell functions during HIV-1 infection

Amu

Ruffin

Réthi

et al. 2013

Aids

Self Cite

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A variety of B-cell dysfunctions are manifested during HIV-1 infection, as reported early during the HIV-1 epidemic. It is not unusual that the pathogenic mechanisms presented to elucidate impairment of B-cell responses during HIV-1 infection focus on the impact of reduced T-cell numbers and functions, and lack of germinal center formation in lymphoid tissues. To our understanding, however, perturbation of B-cell phenotype and function during HIV-1 infection may begin at several different B-cell developmental stages. These impairments can be mediated by intrinsic B-cell defects as well as by the lack of proper T-cell help. In this review, we will highlight some of the pathways and molecular interactions leading to B-cell impairment prior to germinal center formation and B-cell activation mediated through the B-cell receptor in response to HIV-1 antigens. Recent studies indicate a regulatory role for B cells on T-cell biology and immune responses. We will discuss some of these novel findings and how these regulatory mechanisms could potentially be affected by the intrinsic defects of B cells taking place during HIV-1 infection.

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New therapy to revert dysfunctional antibody responses during HIV-1 infection

Cited by 8 publications

References 17 publications

Upregulation of Programmed Death-1 and Its Ligand in Cardiac Injury Models: Interaction with GADD153

Upregulation of Programmed Death-1 and Its Ligand in Cardiac Injury Models: Interaction with GADD153

Immune activation and increased IL‐21R expression are associated with the loss of memory B cells during HIV‐1 infection

Impairment of B-cell functions during HIV-1 infection

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