B‐cell subsets in blood and lymphoid organs in <i>Macaca fascicularis</i>

Vugmeyster, Yulia; Howell, Kathy; Bakshi, A.; Flores, C.; Hwang, Olivia; McKeever, Kathleen

doi:10.1002/cyto.a.20039

Cited by 28 publications

(31 citation statements)

References 42 publications

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“…MZ B cells of cynomolgus monkeys were previously reported to be CD21 hi , CD27 −/+ (Vugmeyster et al, 2004). We confirmed the presence of the CD21 hi phenotype in LN and spleen of rhesus macaques, but not in PBMC (Fig.…”

Section: Resultsmentioning

confidence: 99%

Loss of marginal zone B-cells in SHIVSF162P4 challenged rhesus macaques despite control of viremia to low or undetectable levels in chronic infection

et al. 2015

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Marginal zone (MZ) B cells generate T-independent antibody responses to pathogens before T-dependent antibodies arise in germinal centers. They have been identified in cynomolgus monkeys and monitored during acute SIV infection, yet have not been well-studied in rhesus macaques. Here we characterized rhesus macaque MZ B cells, present in secondary lymphoid tissue but not peripheral blood, as CD19+, CD20+, CD21hi, IgM+, CD22+, CD38+, BTLA+, CD40+, CCR6+ and BCL-2+. Compared to healthy macaques, SHIVSF162P4-infected animals showed decreased total B cells and MZ B cells and increased MZ B cell Ki-67 expression early in chronic infection. These changes persisted in late chronic infection, despite viremia reductions to low or undetectable levels. Expression levels of additional phenotypic markers and RNA PCR array analyses were in concert with continued low-level activation and diminished function of MZ B cells. We conclude that MZ B-cell dysregulation and dysfunction associated with SIV/HIV infection are not readily reversible.

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Section: Resultsmentioning

confidence: 99%

Loss of marginal zone B-cells in SHIVSF162P4 challenged rhesus macaques despite control of viremia to low or undetectable levels in chronic infection

et al. 2015

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“…Memory B-cell subpopulations have been described previously for SIV-infected and uninfected rhesus macaques (8,28,58), SIVinfected sooty mangabeys (58), and SIV-or simian-human immunodeficiency virus (SHIV)-infected and uninfected cynomolgus monkeys (27,46,62). The B-cell subpopulations studied here, defined as either naïve or resting, activated, or tissue-like memory, are similar to those reported previously for SIV-and SHIV-infected animals (27,58).…”

Section: Discussionmentioning

confidence: 99%

Dynamics of Memory B-Cell Populations in Blood, Lymph Nodes, and Bone Marrow during Antiretroviral Therapy and Envelope Boosting in Simian Immunodeficiency Virus SIVmac251-Infected Rhesus Macaques

Demberg

Brocca-Cofano

Xiao

et al. 2012

J Virol

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c Human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) infection causes B-cell dysregulation and the loss of memory B cells in peripheral blood mononuclear cells (PBMC). These effects are not completely reversed by antiretroviral treatment (ART).To further elucidate B-cell changes during chronic SIV infection and treatment, we investigated memory B-cell subpopulations and plasma cells/plasmablasts (PC/PB) in blood, bone marrow, and lymph nodes of rhesus macaques during ART and upon release from ART. Macaques previously immunized with SIV recombinants and the gp120 protein were included to assess the effects of prior vaccination. ART was administered for 11 weeks, with or without gp120 boosting at week 9. Naïve and resting, activated, and tissue-like memory B cells and PC/PB were evaluated by flow cytometry. Antibody-secreting cells (ASC) and serum antibody titers were assessed. No lasting changes in B-cell memory subpopulations occurred in bone marrow and lymph nodes, but significant decreases in numbers of activated memory B cells and increases in numbers of tissue-like memory B cells persisted in PBMC. Macaque PC/PB were found to be either CD27 ؉ or CD27 ؊ and therefore were defined as CD19؉ . The numbers of these PC/PB were transiently increased in both PBMC and bone marrow following gp120 boosting of the unvaccinated and vaccinated macaque groups. Similarly, ASC numbers in PBMC and bone marrow of the two macaque groups also transiently increased following envelope boosting. Nevertheless, serum binding titers against SIVgp120 remained unchanged. Thus, even during chronic SIV infection, B cells respond to antigen, but long-term memory does not develop, perhaps due to germinal center destruction. Earlier and/or prolonged treatment to allow the generation of virus-specific long-term memory B cells should benefit ART/therapeutic vaccination regimens. Early and persistent B-cell dysfunction is a hallmark of human immunodeficiency virus (HIV) infection in humans (11,20,53) and precedes the loss of CD4 ϩ T cells, as shown in the simian immunodeficiency virus (SIV) rhesus macaque model (28). B-cell subpopulations and the expression of cluster-of-differentiation (CD) markers change during early HIV (22, 55) and SIV (28, 46, 58) infections. Patients on highly active antiretroviral therapy (HAART) who control viremia still exhibit B-cell dysregulation, e.g., activation, apoptosis, and abnormal CD marker expression, together with a skewing of B-cell populations, including the continued loss of memory populations and a lower frequency of naïve B cells (4,15,40,48). The early initiation of HAART might be crucial for the preservation of B-cell functionality (37), as HAART treatment has been shown to partially reverse some of these B-cell defects (43,57).Multiple studies have examined virus-specific immune responses in patients or nonhuman primates treated with antiretroviral treatment (ART) or undergoing therapeutic vaccination with or without ART. To mention a few, investigations with humans have included...

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“…Alternatively, others have hypothesized that B-cell depletion is an active process in the circulation and that the apparent tissue depletion is a consequence of the inability to replenish B cells from the blood compartment. [58][59][60] It is important to note that rituximab, despite its failure to completely clear cynomolgus monkey tissue B cells, continues to be a highly effective treatment for many B-cell malignancies.…”

Section: Discussionmentioning

confidence: 99%

The impact of Fc engineering on an anti-CD19 antibody: increased Fcγ receptor affinity enhances B-cell clearing in nonhuman primates

Zalevsky

Leung

Karki

et al. 2009

Blood

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CD19, a B cell-restricted receptor critical for B-cell development, is expressed in most B-cell malignancies. The Fc-engineered anti-CD19 antibody, XmAb5574, has enhanced Fc␥ receptor (Fc␥R) binding affinity, leading to improved Fc␥R-dependent effector cell functions and antitumor activity in murine xenografts compared with the non-Fc-engineered anti-CD19 IgG1 analog. Here, we use XmAb5574 and anti-CD19 IgG1 to further dissect effector cell functions in an immune system closely homologous to that of humans, the cynomolgus monkey. XmAb5574 infusion caused an immediate and dose-related B-cell depletion in the blood (to <10% of baseline levels) concomitant with a sustained reduction of natural killer (NK) cells. NK cells had fully recovered by day 15, whereas B-cell recovery was underway by day 57. B cells in secondary lymphoid tissues were depleted (to 34%-61% of vehicle), with involuted germinal centers apparent in the spleen. Anti-CD19 IgG1 had comparable serum exposure to XmAb5574 but demonstrated no B-cell depletion and no sustained NK-cell reduction. Thus, increasing Fc␥R binding affinity dramatically increased B-cell clearing. We propose that effector cell functions, possibly those involving NK cells, mediate XmAb5574 potency in cynomolgus monkeys, and that enhancing these mechanisms should advance the treatment of B-cell malignancies in humans. IntroductionCD19 is a B cell-restricted signal-transducing cell-surface receptor present on most B cells from the earliest stages of pre-B-cell development until terminal differentiation into plasma cells. 1,2 A critical role for CD19 in B-cell development and activation has been established using CD19-deficient mice. Such mice fail to develop a proper immune response after antigen challenge, exhibit decreased B-cell numbers in the periphery and in lymphoid tissues, lack germinal center (GC) formation, and have decreased serum immunoglobulin (Ig) levels. 1,3,4 Furthermore, anti-CD19 antibodies effectively deplete peripheral B cells in transgenic mice expressing human CD19 and block malignant B-cell growth in murine xenografts. [5][6][7] With the exception of multiple myeloma, 8 CD19 is expressed in nearly all non-Hodgkin lymphomas and many leukemias. 9,10 Several anti-CD19 antibodies have been evaluated in the clinic for the treatment of such diseases, including unconjugated antibodies, 11,12 antibody-drug conjugates, 13,14 and bispecific antibodies targeting CD19 and CD3. 15,16 Despite the attractiveness of CD19 as an immunotherapeutic target for the treatment of B-cell malignancies, the results with patients have been mixed. Thus, the challenge remains to optimize anti-CD19 antibodies to achieve improved clinical outcome.The potency of immunotherapeutics depends on multiple mechanisms of action, including those mediated by effector cells expressing Fc␥ receptors (Fc␥Rs). 17 Fc␥Rs in turn have activating or inhibitory functional roles and differ in their distribution among effector cells. Monocytes, macrophages, and neutrophils express both activating and inhibitor...

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B‐cell subsets in blood and lymphoid organs in Macaca fascicularis

Cited by 28 publications

References 42 publications

Loss of marginal zone B-cells in SHIVSF162P4 challenged rhesus macaques despite control of viremia to low or undetectable levels in chronic infection

Loss of marginal zone B-cells in SHIVSF162P4 challenged rhesus macaques despite control of viremia to low or undetectable levels in chronic infection

Dynamics of Memory B-Cell Populations in Blood, Lymph Nodes, and Bone Marrow during Antiretroviral Therapy and Envelope Boosting in Simian Immunodeficiency Virus SIVmac251-Infected Rhesus Macaques

The impact of Fc engineering on an anti-CD19 antibody: increased Fcγ receptor affinity enhances B-cell clearing in nonhuman primates

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