Hematopoietic mobilization

Abstract

Objective: To ascertain the mobilization from the bone marrow and the functional relevance of the increased number of circulating hematopoietic stem and progenitor cells (HSPC) induced by the anti-a-4 integrin antibody natalizumab in patients with multiple sclerosis (MS).Methods: We evaluated CD45 low CD341 HSPC frequency by flow cytometry in blood from 45 natalizumab-treated patients (12 of whom were prospectively followed during the first year of treatment as part of a pilot cohort and 16 prospectively followed for validation), 10 untreated patients with MS, and 24 healthy donors. In the natalizumab-treated group, we also assessed sorted HSPC cell cycle status, T-and B-lymphocyte subpopulation frequencies (n 5 29), and HSPC differentiation potential (n 5 10).Results: Natalizumab-induced circulating HSPC were predominantly quiescent, suggesting recent mobilization from the bone marrow, and were capable of differentiating ex vivo. Circulating HSPC numbers were significantly increased during natalizumab, but heterogeneously, allowing the stratification of mobilizer and nonmobilizer subgroups. Nonmobilizer status was associated with persistence of disease activity during treatment. The frequency of B cells and CD1031CD81 regulatory T cells persistently increased, more significantly in mobilizer patients, who also showed a specific naive/memory B-cell profile. Conclusions:The data suggest that natalizumab-induced circulating HSPC increase is the result of true mobilization from the bone marrow and has clinical and immunologic relevance. HSPC mobilization, associated with clinical remission and increased proportion of circulating B and regulatory T cells, may contribute to the treatment's mode of action; thus, HSPC blood counts could represent an early biomarker of responsiveness to natalizumab. Multiple sclerosis (MS) is thought to be initiated by inflammatory blood-derived leukocytes entering the CNS. a4b1 integrin plays a key role in leukocyte trafficking 1 ; its a4 subunit is targeted by the MS treatment natalizumab, which suppresses brain MRI lesion formation and reduces relapse rate.2-4 Improvement of neurologic function in treated patients has also been observed.5-7 Natalizumab's anti-inflammatory effect in CNS is mirrored by a radical decrease of lymphocyte number in the CSF 8,9 and by T-cell sequestration in the periphery, 10,11 yet less is known about its effects on B cells and on hematopoietic stem and progenitor cells (HSPC) recirculation, both cell types expressing a4b1. Natalizumab treatment induces a significant and protracted peripheral HSPC increase in the blood of patients with MS.12,13 The mechanism and the functional significance of the observed increase, however, remain poorly understood.

Natalizumab treatment leads to an increase in circulating CXCR3-expressing B cells

“…This results with increased numbers of circulating B cells as shown in this study and by others. 6,7 Our result of the apparent partial decrease in B cell VLA-4 expression following natalizumab treatment is in line with previous results. 8 In addition to adhesion molecules, chemokine receptors and chemokines contribute to recruitment of leukocytes into sites of inflammation.…”

“…6,7 This phenomenon is so pronounced that it leads to an increase in absolute numbers of any B cell population studied (table). However, when proportions of various B cell subpopulations are calculated, the only increase is observed in CXCR3-expressing B cells.…”

Natalizumab treatment leads to an increase in circulating CXCR3-expressing B cells

“…This results with increased numbers of circulating B cells as shown in this study and by others. 6,7 Our result of the apparent partial decrease in B cell VLA-4 expression following natalizumab treatment is in line with previous results. 8 In addition to adhesion molecules, chemokine receptors and chemokines contribute to recruitment of leukocytes into sites of inflammation.…”

“…6,7 This phenomenon is so pronounced that it leads to an increase in absolute numbers of any B cell population studied (table). However, when proportions of various B cell subpopulations are calculated, the only increase is observed in CXCR3-expressing B cells.…”

Erythroblastaemia in natalizumab-treated patients with multiple sclerosis

“…Nevertheless, it is not yet clear whether higher levels of NRBCs might have long term implications for these patients. The values of CD 34þ cells detected in NTZ patients are consistent with previous reports (Zohren et al, 2008;Mattoscio et al, 2015) and suggest a natalizumab-triggered mobilization of haematopoietic stem cells from the bone marrow. The absence of correlation between NRBCs counts in natalizumabtreated patients and the number of infusions supports the hypothesis that haematopoietic stem cell concentrations do not differ significantly between the first doses and the chronic treatment (Zohren et al, 2008;Bonig et al, 2008), even if a longitudinal observation on a wider population should be performed to confirm this result.…”

CCN3 is dynamically regulated by treatment and disease state in multiple sclerosis

“…Preliminary work indicated that CCN3 could stimulate mobilised adult CD34 + cells in similar ways [ 17 ]. In MS patients treated with natalizumab, persistent MRI and clinical disease activity occurred in patients that lacked HSC mobilisation post-treatment [ 46 ]. Understanding the role of CCN3 in adult HSC and peripheral immune cells could reveal important insights for MS.…”

Natalizumab treatment leads to an increase in circulating CXCR3-expressing B cells

“…This results with increased numbers of circulating B cells as shown in this study and by others. 6,7 Our result of the apparent partial decrease in B cell VLA-4 expression following natalizumab treatment is in line with previous results. 8 In addition to adhesion molecules, chemokine receptors and chemokines contribute to recruitment of leukocytes into sites of inflammation.…”

“…6,7 This phenomenon is so pronounced that it leads to an increase in absolute numbers of any B cell population studied (table). However, when proportions of various B cell subpopulations are calculated, the only increase is observed in CXCR3-expressing B cells.…”

Erythroblastaemia in natalizumab-treated patients with multiple sclerosis

“…Nevertheless, it is not yet clear whether higher levels of NRBCs might have long term implications for these patients. The values of CD 34þ cells detected in NTZ patients are consistent with previous reports (Zohren et al, 2008;Mattoscio et al, 2015) and suggest a natalizumab-triggered mobilization of haematopoietic stem cells from the bone marrow. The absence of correlation between NRBCs counts in natalizumabtreated patients and the number of infusions supports the hypothesis that haematopoietic stem cell concentrations do not differ significantly between the first doses and the chronic treatment (Zohren et al, 2008;Bonig et al, 2008), even if a longitudinal observation on a wider population should be performed to confirm this result.…”

CCN3 is dynamically regulated by treatment and disease state in multiple sclerosis

“…Preliminary work indicated that CCN3 could stimulate mobilised adult CD34 + cells in similar ways [ 17 ]. In MS patients treated with natalizumab, persistent MRI and clinical disease activity occurred in patients that lacked HSC mobilisation post-treatment [ 46 ]. Understanding the role of CCN3 in adult HSC and peripheral immune cells could reveal important insights for MS.…”

Natalizumab treatment leads to an increase in circulating CXCR3-expressing B cells

“…This results with increased numbers of circulating B cells as shown in this study and by others. 6,7 Our result of the apparent partial decrease in B cell VLA-4 expression following natalizumab treatment is in line with previous results. 8 In addition to adhesion molecules, chemokine receptors and chemokines contribute to recruitment of leukocytes into sites of inflammation.…”

“…6,7 This phenomenon is so pronounced that it leads to an increase in absolute numbers of any B cell population studied (table). However, when proportions of various B cell subpopulations are calculated, the only increase is observed in CXCR3-expressing B cells.…”

Erythroblastaemia in natalizumab-treated patients with multiple sclerosis

“…Nevertheless, it is not yet clear whether higher levels of NRBCs might have long term implications for these patients. The values of CD 34þ cells detected in NTZ patients are consistent with previous reports (Zohren et al, 2008;Mattoscio et al, 2015) and suggest a natalizumab-triggered mobilization of haematopoietic stem cells from the bone marrow. The absence of correlation between NRBCs counts in natalizumabtreated patients and the number of infusions supports the hypothesis that haematopoietic stem cell concentrations do not differ significantly between the first doses and the chronic treatment (Zohren et al, 2008;Bonig et al, 2008), even if a longitudinal observation on a wider population should be performed to confirm this result.…”

CCN3 is dynamically regulated by treatment and disease state in multiple sclerosis

“…Preliminary work indicated that CCN3 could stimulate mobilised adult CD34 + cells in similar ways [ 17 ]. In MS patients treated with natalizumab, persistent MRI and clinical disease activity occurred in patients that lacked HSC mobilisation post-treatment [ 46 ]. Understanding the role of CCN3 in adult HSC and peripheral immune cells could reveal important insights for MS.…”