Natalizumab and Impedance of the Homing of CD34⁺ Hematopoietic Progenitors

Abstract

Background: Treatment with natalizumab, an antibody blocking the ␣4-integrin, is associated with increased numbers of circulating CD34 ϩ cells in the peripheral blood of patients with multiple sclerosis. Objective: To determine whether natalizumab mobilizes CD34 ϩ cells from or inhibits homing to the bone marrow (BM). Design: Fifty-two patients with relapsing-remitting multiple sclerosis treated with natalizumab were included. Flow cytometric analyses; polymerase chain reaction assays for JC (John Cunningham) virus DNA detection; and adhesion, migration, and apoptosis assays of immunomagnetically enriched peripheral blood and BM CD34 ϩ cells were conducted. A comparison was made with CD34 ϩ cells from granulocyte colony-stimulating factor-mobilized peripheral blood or steady-state BM of age-and sex-matched healthy donors. Results: We found adhesion and migration of peripheral blood-derived CD34 ϩ cells to be reduced. In BM aspirates from natalizumab-treated patients, the cellularity, the proportion, and the adhesive capacity of CD34 ϩ cells were normal. The JC virus was undetectable. Conclusions: Natalizumab mediates an increase in circulating CD34 ϩ cells by interfering with homing to the BM. Thus, CD34 ϩ cells appear unlikely to represent a source mobilizing JC virus out of the BM in patients treated with natalizumab.

Hematopoietic mobilization

“…Thus this evidence strongly suggests an augmented rate of egress from the bone marrow, therefore a true mobilization effect of the drug, as hypothesized by us and previously, 17 yet does not rule out the potential contribution of a natalizumab-mediated impaired homing of HSPC to the bone marrow. 18 Moreover, we confirmed the healthy state of the bone marrow compartment in MS and showed that natalizumab-mobilized HSPC retain full capacity to expand and differentiate; therefore their increase in the circulation may have biological effects.…”

Hematopoietic mobilization

“…Thus this evidence strongly suggests an augmented rate of egress from the bone marrow, therefore a true mobilization effect of the drug, as hypothesized by us and previously, 17 yet does not rule out the potential contribution of a natalizumab-mediated impaired homing of HSPC to the bone marrow. 18 Moreover, we confirmed the healthy state of the bone marrow compartment in MS and showed that natalizumab-mobilized HSPC retain full capacity to expand and differentiate; therefore their increase in the circulation may have biological effects.…”

JC virus reactivation during prolonged natalizumab monotherapy for multiple sclerosis

“…The ability of JCV to infect CD34 + cells and B lymphocytes, has clearly been demonstrated in vitro 33–35 , but to date JCV has not been found in CD34 + cells from clinical specimens of HIV-infected or natalizumab-treated patients 36–38 . In recent studies, Saure et al 37 and Warnke et al 38 did not detect JCV in CD34 + cells obtained from bone marrow or blood, respectively, of natalizumab-treated patients. However, in the former study 37 JCV PCR was performed in only 9 MS natalizumab-treated patients; in the latter study 38 the average number of natalizumab infusions was approximately twelve.…”

“…In recent studies, Saure et al 37 and Warnke et al 38 did not detect JCV in CD34 + cells obtained from bone marrow or blood, respectively, of natalizumab-treated patients. However, in the former study 37 JCV PCR was performed in only 9 MS natalizumab-treated patients; in the latter study 38 the average number of natalizumab infusions was approximately twelve.…”

Effects of disease-modifying therapy on peripheral leukocytes in patients with multiple sclerosis

“…Natalizumab, an anti-α4 integrin monoclonal antibody, prevents lymphocyte migration through the blood-brain barrier into the CNS [49]. In contrast to the other immunosuppressive DMTs discussed in this review that associate with lymphopenia, natalizumab treatment leads to a considerable increase in peripheral blood of CD4+ and CD8+ T cells, CD19+ B cells, and NK cells in the peripheral blood, due to elevated release or impaired homing of lymphocytes, including the CD34+ progenitor cells subpopulation, from or to the bone marrow and secondary lymphoid tissues, respectively [50,51]. Compartmentalized effects are noted, with the total number of lymphocytes in the cerebrospinal fluid (CSF) being dramatically reduced and a diminution of the CD4+/ CD8+ ratio.…”

Hematopoietic mobilization

“…Thus this evidence strongly suggests an augmented rate of egress from the bone marrow, therefore a true mobilization effect of the drug, as hypothesized by us and previously, 17 yet does not rule out the potential contribution of a natalizumab-mediated impaired homing of HSPC to the bone marrow. 18 Moreover, we confirmed the healthy state of the bone marrow compartment in MS and showed that natalizumab-mobilized HSPC retain full capacity to expand and differentiate; therefore their increase in the circulation may have biological effects.…”

JC virus reactivation during prolonged natalizumab monotherapy for multiple sclerosis

“…The ability of JCV to infect CD34 + cells and B lymphocytes, has clearly been demonstrated in vitro 33–35 , but to date JCV has not been found in CD34 + cells from clinical specimens of HIV-infected or natalizumab-treated patients 36–38 . In recent studies, Saure et al 37 and Warnke et al 38 did not detect JCV in CD34 + cells obtained from bone marrow or blood, respectively, of natalizumab-treated patients. However, in the former study 37 JCV PCR was performed in only 9 MS natalizumab-treated patients; in the latter study 38 the average number of natalizumab infusions was approximately twelve.…”

“…In recent studies, Saure et al 37 and Warnke et al 38 did not detect JCV in CD34 + cells obtained from bone marrow or blood, respectively, of natalizumab-treated patients. However, in the former study 37 JCV PCR was performed in only 9 MS natalizumab-treated patients; in the latter study 38 the average number of natalizumab infusions was approximately twelve.…”

Effects of disease-modifying therapy on peripheral leukocytes in patients with multiple sclerosis

“…Natalizumab, an anti-α4 integrin monoclonal antibody, prevents lymphocyte migration through the blood-brain barrier into the CNS [49]. In contrast to the other immunosuppressive DMTs discussed in this review that associate with lymphopenia, natalizumab treatment leads to a considerable increase in peripheral blood of CD4+ and CD8+ T cells, CD19+ B cells, and NK cells in the peripheral blood, due to elevated release or impaired homing of lymphocytes, including the CD34+ progenitor cells subpopulation, from or to the bone marrow and secondary lymphoid tissues, respectively [50,51]. Compartmentalized effects are noted, with the total number of lymphocytes in the cerebrospinal fluid (CSF) being dramatically reduced and a diminution of the CD4+/ CD8+ ratio.…”

Hematopoietic mobilization

“…Thus this evidence strongly suggests an augmented rate of egress from the bone marrow, therefore a true mobilization effect of the drug, as hypothesized by us and previously, 17 yet does not rule out the potential contribution of a natalizumab-mediated impaired homing of HSPC to the bone marrow. 18 Moreover, we confirmed the healthy state of the bone marrow compartment in MS and showed that natalizumab-mobilized HSPC retain full capacity to expand and differentiate; therefore their increase in the circulation may have biological effects.…”

JC virus reactivation during prolonged natalizumab monotherapy for multiple sclerosis

“…The ability of JCV to infect CD34 + cells and B lymphocytes, has clearly been demonstrated in vitro 33–35 , but to date JCV has not been found in CD34 + cells from clinical specimens of HIV-infected or natalizumab-treated patients 36–38 . In recent studies, Saure et al 37 and Warnke et al 38 did not detect JCV in CD34 + cells obtained from bone marrow or blood, respectively, of natalizumab-treated patients. However, in the former study 37 JCV PCR was performed in only 9 MS natalizumab-treated patients; in the latter study 38 the average number of natalizumab infusions was approximately twelve.…”

“…In recent studies, Saure et al 37 and Warnke et al 38 did not detect JCV in CD34 + cells obtained from bone marrow or blood, respectively, of natalizumab-treated patients. However, in the former study 37 JCV PCR was performed in only 9 MS natalizumab-treated patients; in the latter study 38 the average number of natalizumab infusions was approximately twelve.…”

Effects of disease-modifying therapy on peripheral leukocytes in patients with multiple sclerosis

“…Natalizumab, an anti-α4 integrin monoclonal antibody, prevents lymphocyte migration through the blood-brain barrier into the CNS [49]. In contrast to the other immunosuppressive DMTs discussed in this review that associate with lymphopenia, natalizumab treatment leads to a considerable increase in peripheral blood of CD4+ and CD8+ T cells, CD19+ B cells, and NK cells in the peripheral blood, due to elevated release or impaired homing of lymphocytes, including the CD34+ progenitor cells subpopulation, from or to the bone marrow and secondary lymphoid tissues, respectively [50,51]. Compartmentalized effects are noted, with the total number of lymphocytes in the cerebrospinal fluid (CSF) being dramatically reduced and a diminution of the CD4+/ CD8+ ratio.…”