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Stem Cells, Vol. 18, No. 6, 390-398, November 2000
© 2000 AlphaMed Press

Concise Review

Immunologic Profiles of Effector Cells and Peripheral Blood Stem Cells Mobilized with Different Hematopoietic Growth Factors

Yair Gazitt

University of Texas, Health Science Center, San Antonio, Texas, USA

Key Words. Mobilization • CD34+ cells • VLA-4 • L-Selectin • CXCR4

Yair Gazitt, Ph.D., Department of Medicine/Hematology, University of Texas Health Science Center, 7703 Floyd Curl Dr., San Antonio, TX 78284, USA.


   ABSTRACT
Top
 Abstract
Introduction
 References
 
Background. Peripheral blood stem cells (PBSC) have become the preferred source of stem cells for autologous transplantation because of the technical advantage and the shorter time to engraftment. Mobilization of CD34+ cells into the peripheral blood can be achieved by the administration of G-CSF or GM-CSF, or both, alone or in combination with chemotherapy. G-CSF and GM-CSF differ somewhat in the number and composition of CD34+ cells and effector cells mobilized to the peripheral blood. However, the molecular mechanism underlying the release and engraftment of CD34+ cells is poorly understood.

Purpose. The purpose of this review is to give a recent update on the type and immunological properties of effector cells and CD34+ cells mobilized by the different growth factors with emphasis on A) mobilization of T cells, natural killer cells, and dendritic cells; B) coexpression of adhesion molecules such as VLA-4 and L-selectin in mobilized PBSC collection, and C) coexpression of CXCR4—the receptor for the stromal-derived differentiation factor 1—with latest information shedding light on the molecular mechanism underlying the release and subsequent engraftment of CD34+ cells.

Conclusions. A) The reported suppression of T cell and NK cell functions in PBSC apheresis collections in patients primed with G-CSF or GM-CSF is controversial and may merely reflect low effector cell activity before mobilization. B) A decrease in the expression of adhesion molecules such as VLA-4 and L-selectin is a necessary requirement for the release of CD34+ cells to the peripheral blood. C) A decrease in the expression of CXCR4 is a necessary requirement for the release of CD34+ cells to the peripheral blood and correlates with mobilization success.


   INTRODUCTION
Top
 Abstract
 Introduction
References
 
Autologous peripheral blood stem cells (PBSC) provide a rapid and sustained hematopoietic recovery after the administration of high-dose chemotherapy or chemoradiotherapy in patients with hematological malignancies. PBSC have become the preferred source of stem cells for autologous transplantation because of the shorter time to engraftment and the lack of a need for surgical procedure necessary for bone marrow harvesting [1-6].

Mobilization of CD34+ PBSC can be achieved by the administration of G-CSF or GM-CSF, alone [3, 6-8] or in combination with chemotherapy, in which case a higher yield of CD34+ cells can be obtained with a shortening of the number of collections to achieve the minimal dose of CD34+ cells required for prompt engraftment [9-16]. Recent studies advocate the use of a concurrent or sequential combination of G-CSF and GM-CSF, which appear to be superior over one growth factor alone, in normal allogeneic donors [17, 18]. In cancer patients, however, some reports suggest an advantage for mobilization in patients receiving GM-CSF plus G-CSF for mobilization, over one growth factor [19]. Other reports did not find an advantage for GM-CSF plus G-CSF over G-CSF, when growth factors alone were used [20, 21]. Our own experience in a randomized study of non-Hodgkin's lymphoma (NHL) patients suggests similar mobilization efficacies for G-CSF, GM-CSF, or sequential GM-CSF followed by G-CSF in patients primed with cyclophosphamide [22].

It is widely accepted that G-CSF mobilizes higher numbers of nucleated cells, the majority of which are granulocytes, whereas GM-CSF mobilizes smaller numbers of nucleated cells, predominantly CD14+ monocytes. However, the effect of G-CSF and GM-CSF on the mobilization of natural killer (NK) cells, T cells, dendritic cells, and subpopulations of CD34+ cells is not yet clear. In this review, the latest information regarding mobilization and function of T cells, NK cells, and CD34+ cell subpopulations will be presented with a special emphasis on adhesion molecules and the coexpression of chemotaxis receptors on CD34+ cells, in the context of the release and homing of CD34+ cells.

Mobilization of T Cells and NK Cells
NK cells and T cells are the major effector cells involved in anticancer immune response. Several reports demonstrated that treatment with hematopoietic growth factors, in the context of stem cell mobilization, results in suppression of T cell and NK cell functions, both in normal allogeneic donors and in cancer patients. Others reported stimulation of effector cell activity in mobilized PBSC collections. Thus, reports by Ageitos et al. [23, 24] and Reyes et al. [25] described a decrease in the activity of T cells and NK cells in the PBSC collections in various cancer patients mobilized with G-CSF, and Shibuya et al. [26] and Taga et al. [27] reported a decrease in T cell and NK cell function in patients with aplastic anemia and myelodysplastic syndrome mobilized with G-CSF. Similar results were obtained by Rondelli et al. [28], Hassan et al. [29], and Miller et al. [30] in normal donors. However, Silva et al. [31] did not find a decrease in T cell or NK cell activity in cancer patients mobilized with G-CSF, compared with baseline, premobilization activity. Other groups used GM-CSF to mobilize PBSC and reported either suppression [24, 26, 32], or activation [33-35] of T cell and NK cell activity. As a result of these contradictory results, it is not clear whether G-CSF or GM-CSF have any in vivo effect on effector cells. These inconsistencies are probably due to the small number of patients, or normal donors, used in these studies, and the fact that in all cases except one, baseline NK and T cell functions were not compared with the activity in the PBSC collection of the same patient.

Recently, we performed a prospective, randomized three-arm study to compare the effect of G-CSF, GM-CSF, or sequential GM-CSF followed by G-CSF on NK cells and NK activity in 35 NHL patients [36]. We observed a great heterogeneity in the amount of NK cell mobilization between different patients, ranging between a 0- to 10-fold increase above the baseline of premobilization peripheral blood (Fig. 1Go). The maximum amount of CD56+ cells was observed on day 2 and day 3 of collection, with a substantial decline on day 4 in most patients. The levels of CD56+ cells further declined in samples taken six months after transplant (~1.1 x 106 cells/kg), reaching the baseline levels observed in premobilization peripheral (1-2 x 106 cells/kg) and close to the amount observed in four normal controls (0.5 x 106 ± 0.14 cells/kg; horizontal line). The correlation between CD56+ NK cells and NK activity in PBSC collections is depicted in Figure 1Go (left inset). Maximal lysis values and maximal CD56+ cells/kg were used for this correlation study. We found no difference in the activity or numbers of CD56+ NK cells and NK activity between the three arms of the study, but rather, we observed a strong correlation between CD56+ cells and NK activity, and between pre- and postmobilization NK activity, in the apheresis collections of these patients (Fig. 1Go, right inset). Thus, it appears from our study that patients with relatively low NK cell or NK activity in the baseline before mobilization had low NK activity in the PBSC collections. Therefore, in the absence of a baseline T cell or NK cell activity, patient-to-patient variability should be taken into consideration in the interpretation of previous studies regarding the effect of growth factors on the numbers and function of T cells or NK cells in PBSC collections. Of interest in this respect are recent findings that interleukin 2 (IL-2) stimulates NK activity in vitro in PBSC collections of patients primed with G-CSF [33] and in PBSC collections from mice primed with stem cell factor (SCF) [37]. Similarly, Joshi et al. [38] reported recently the results from a clinical trial suggesting that addition of erythropoietin to G-CSF-primed patients preserves the immunological functions of effector cells in the PBSC collection. These results indicate that effector cells in mobilized peripheral blood can maintain their immunological potential in the presence of the proper costimulatory growth factors. Finally, even if the in vitro findings suggesting some suppressive effect of G-CSF and GM-CSF on the mobilization and function of NK cells and T cells were found to be correct, no follow-up studies were reported proving any clinical correlation between the potency of the effector cells in PBSC collections and the clinical outcome for patients undergoing high-dose chemotherapy and stem cell rescue. In fact, in our study, in a median follow-up of >1 yr, we could not find differences in the relapse rate or survival between patients with high or low NK activity in their PBSC collections [36].



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  		Figure 1. Mobilization of CD56+ NK cells. Staining and analysis of results was performed as described before CD34+/CD45dim cells [22], except for the paired antibodies. For NK cells, anti-CD56-PE (Immunotech; Marseilles, France) and anti-CD16-FITC (Caltag; Burlingame, CA) were used. NK cells were defined as the sum of CD56+ and CD56+CD16+ cells. NK activity was determined by the 4-h chromium-release assay using K562 erythroleukemia cells as target cell as described before [89]. Effector:Target (E:T) ratios of 40:1, 20:1, 10:1, and 5:1 were used against 5,000 target cells in a final volume of 0.25 ml/well of the above culture medium. Incubations and analysis of results were done as previously described. Results obtained from 27 patients in the three arms of the study are depicted. (For details regarding study design, patient population, stem cell mobilization, and stem cell collection [22]). Samples were collected before mobilization (B), during four collections (d1 to d4), and 6 mo posttransplant (F1). Bars represent standard deviation. A daily increase in the amount of CD56+ NK cells/kg, above baseline levels of steady-state peripheral blood (PB) was observed in the apheresis collections. The results were derived from 25 patients. The correlation between NK activity and CD56+ cells in the apheresis collections is shown in Figure 1Go, left inset. The correlation between NK activity in the peripheral blood before and after mobilization is shown in Figure 1Go, right inset. Maximal lysis values were used for this study. Similar results were obtained when data were analyzed as NK cell/µl (Y. Gazitt, unpublished observations).

 
Mobilization of Dendritic Cells
Dendritic cells constitute the most effective antigen presenting cells and therefore are the most important regulatory element of the cellular immune response [39]. Differentiation to dendritic cells can be induced from CD14+ monocytes using IL-4 and GM-CSF [40], or from CD34+ cells by a great variety of growth factors such as GM-CSF plus tumor necrosis factor-{alpha} (TNF-{alpha}) [41, 42], SCF plus GM-CSF and IL-4 or TNF-{alpha} [43-45], IL-13 [46], IL-15 [47], and flt3 ligand with TGF-ß [48, 49].

Recently, CD80, CD83, CD86, and CD1a antigens were identified as relatively specific for dendritic cells with a different degree of maturity and were shown to be important for dendritic cell function [39, 50, 51]. More recently, antitumor vaccines were developed based on specific stimulation of dendritic cells [39, 52-59] and, therefore, dendritic cells became an important tool in the immunotherapy of cancer.

GM-CSF-containing protocols are the preferred protocols for generation of dendritic cells in vitro. Previous publication by Avigan et al. [60] compared mobilization of precursor dendritic cells by G-CSF alone, or in combination with GM-CSF, in breast cancer patients undergoing stem cell mobilization for autotransplantation. They quantitated the number and function of mature dendritic cells generated in vitro from nonadherent CD14+ cells in the PBSC collections following treatment with GM-CSF plus IL-4. They detected an increase in the mobilization of dendritic precursor cells in patients mobilized with GM-CSF plus G-CSF, however, mobilization of CD80+ dendritic cells was not studied [60]. Morse et al. [61] compared the efficacy of G-CSF, with and without cyclophosphamide (Cy) to generate precursors for dendritic cells, using a similar approach for determination of in vitro differentiation of CD14+ precursor cells to mature dendritic cells. They reported no increase in the number of dendritic precursor cells in Cy-containing regimens assayed in vitro using GM-CSF and IL-4 [61]. In a very recent study, Roth et al. [62] compared the effect of administration of GM-CSF alone to GM-CSF plus increasing doses of IL-4, on the generation of CD14+ cells and CD83+ dendritic cells in patients with metastatic solid tumors. They found clear synergy between GM-CSF and high doses of IL-4 in mobilization of circulating CD14+ and CD83+ cells and in dendritic cell-induced specific stimulation of T-cell proliferation. Recently, we performed a prospective, randomized three-arm study to compare the effect of G-CSF, GM-CSF, or sequential GM-CSF followed by G-CSF on the mobilization of CD80+ and CD80+CD14+ dendritic cells in 35 NHL patients undergoing high-dose chemotherapy and peripheral blood stem cell rescue [36]. In a recent study, we observed a 3- to 10-fold increase in dendritic precursor cell mobilization in patients receiving GM-CSF-containing regimens over G-CSF alone. Figure 2Go depicts the amounts of CD80+ dendritic cells mobilized by 35 patients in the three arms of the study. A daily increase in the amount of dendritic cells was observed in the apheresis collections with a maximal amount observed between day 2 and day 4 of collection, compared with premobilization levels. Six months after transplant, the levels of CD80+ dendritic cells returned to premobilization levels (Fig. 2Go). Most importantly, a clear difference was observed between the three arms of the study. Mobilization with Cy + G-CSF resulted with a maximum of 2.4 ± 0.3 x 106 CD80+ cells/kg on day 3 and day 4 of collection, compared with <1 x 106 cells/kg, observed in premobilization peripheral blood. Mobilization with Cy + GM-CSF resulted with the highest number of dendritic cells (9.4 ± 1.3 x 106 CD80+ cells/kg) on day 3 of collection. Mobilization with GM-CSF/G-CSF resulted in an intermediate collection of 4.8 ± 0.9 x 106 cells/kg on day 3 and day 4. The levels of CD80+ dendritic cells returned to premobilization levels and close to the level observed in four normal controls (1 x 106 cells/kg; horizontal line in Fig. 2Go). Analysis of variance between the three arms revealed statistically significant differences (G-CSF versus GM-CSF, p = 0.005; G-CSF versus GM-CSF/G-CSF, p = 0.04; GM-CSF versus GM-CSF/G-CSF, p = 0.01) (Fig. 2Go).



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  		Figure 2. Mobilization of CD80+CD14+ dendritic cells. For dendritic cells anti-CD80-FITC (Immunotech) and CD14-PE (Caltag) were used. Other experimental conditions are as in Figure 1Go. Dendritic cells were defined as the sum of CD80+ and CD80+CD14+ cells (mature and immature dendritic cells). The results obtained from 35 patients in the three arms of the study are depicted. (For details regarding study design, patient population, stem cell mobilization, and stem cell collection [22]). Peripheral blood samples were taken before mobilization (B), during four collections (d1 to d4), and 6 mo posttransplant (F1). Bars represent SD. Similar results were obtained when data were analyzed as NK cell/µl (Y. Gazitt, unpublished observations).

 
At this point, it is not clear from our study, or from studies by others, whether mobilization of higher numbers of dendritic precursor cells has any clinical advantage over patients with low precursor dendritic cells in their PBSC products, in the context of PBSC transplantation. However, higher numbers of precursor dendritic cells in the PBSC collections in patients mobilized with regimens containing GM-CSF should be advantageous for protocols involving in vivo or in vitro manipulation of dendritic cells for the generation of specific antitumor vaccines—an area with a growing interest.

Mobilization of CD34+ Subsets
CD34+ cells contain mostly hematopoietic progenitor cells, with relatively low potential for self-renewal in vitro and in vivo, compared with CD34+ cell subsets, such as CD34+CD33– cells [63], CD34+CD38– cells [64, 65], and CD34+Thy1+ cells [66, 67]. These CD34+ cell subsets are considered more primitive hematopoietic stem cells, with a capability of self-renewal in vitro and in vivo in a SCID mouse model [65, 68] and in humans [16]. GM-CSF is considered a better mobilizer of CD34+CD38– cells [69] and CD34+Thy1+ stem cell subsets [22].

The area of primitive CD34+ cell subsets has been reviewed extensively in the last few years [70, 71] and therefore, this review will deal with coexpression of adhesion molecules and chemokine receptors on CD34+ cells, in the context of CD34+ cell release from the bone marrow to the peripheral blood.

Mobilization of CD34+ Cells Coexpressing Adhesion Molecules
CD34+ cells in PBSC apheresis collections coexpress several adhesion molecules, the most studied of which are CD49d (VLA-4) and CD62L (L-selectin) [72-77] and anti-VCAM-1 [78]. In particular, VLA-4 and VCAM-1 are directly involved in the release of CD34+ cells to the peripheral blood because in vivo treatment of mice with antibodies to VLA-4 or VCAM-1 was capable of inducing mobilization of CD34+ stem cells [78, 79]. Furthermore, Zeller et al. [80] reported an inverse correlation between the amount of CD34+ cells mobilized and the extent of coexpression of CD34+VLA-4+ cells. Others also reported a decrease of VLA-4 expression in mobilized peripheral blood [72, 74-80]. In a recent study, we, like others, observed a decrease in the coexpression of VLA-4 on CD34+ cells in the apheresis collections of 35 NHL patients compared with CD34+ cells in the steady-state bone marrow (Gazitt et al., submitted). In addition, we, like others, observed a strong decrease in the expression of L-selectin on CD34+ cells in the PBSC apheresis collections, compared with the steady-state bone marrow. Decreases in the expression of VLA-4 and L-selectin on CD34+ cells were observed in the apheresis collections of all patients, regardless of the growth factor used for mobilization (Gazitt et al., submitted). Our results are consistent with results obtained by other groups [72, 74-80]. Therefore, a decrease in the expression of adhesion molecules such as VLA-4 and L-selectin appears to be a necessary requirement for the release of CD34+ cells to the peripheral blood. However, it is important to note that hematopoietic growth factors can affect the growth and activity of CD34+ cells [81]. Similarly, focal adhesion kinases and focal adhesion contacts may contribute to the expression and activity of hematopoietic stem cells [82].

Mobilization of CD34+ Cells Coexpressing SDF-1 Receptor
CXCR4 is the receptor for the stromal cell-derived factor 1 (SDF-1) and is coexpressed on CD34+ cells [83-86] and these cells migrate across a gradient of SDF-1 concentration, in vitro and in vivo [87, 88]. Also, the expression of CXCR4 was implicated in the process of CD34+ stem cell migration and engraftment, in vitro and in vivo, in a mouse model [87]. It has also been shown that SDF-1 alone, or in combination with other growth factors, induces proliferation of CD34+ cells [86]. However, to date, no studies were reported comparing the efficiency of CD34+ cell mobilization in relation to the expression of CXCR4 in a controlled prospective study of mobilization by different growth factors. In recent studies, we determined the level of coexpression of CXCR4 on CD34+ cells in the apheresis collections of 35 NHL patients mobilized with G-CSF (arm A), GM-CSF (arm B), or sequential GM-CSF followed by G-CSF (arm C) [89]. We observed a significant decrease in the expression of CXCR4 in PBSC collections compared with steady-state bone marrow, irrespective of the growth factor used for mobilization. As outlined in Figure 3Go, the mean percentage of cells coexpressing CXCR4/CD34 in the bone marrow (BM) was 28 ± 11.2%, 26.5 ± 12.6%, and 26.4 ± 7.1% in patients in arms A, B, and C, respectively. In contrast, the mean percentage of cells coexpressing CXCR4/CD34 in the PB was 21.7 ± 8.6%, 18.6 ± 11.3%, and 22.6 ± 4.9% in patients in arms A, B, and C, respectively. The mean percentage of cells coexpressing CXCR4/CD34 was significantly lower in the four apheresis collections (17.3 ± 2.8%, 21.4 ± 3.1%, and 17 ± 2.8%) in patients in arms A, B, and C, respectively (BM versus PBSC; p = 0.03), with no major differences observed between the different days of collection or between the three arms of the study (Fig. 3AGo). Furthermore, when the patients were regrouped as "good mobilizers" and "poor mobilizers" (Fig. 3BGo), a statistically significant difference in the percentage of cells coexpressing CXCR4/CD34 was observed between the PBSC collections in the two groups of patients. The mean percentage of cells coexpressing CXCR4/CD34 in the four collections of the "good mobilizers" was 15.6 ± 2.1%, compared with 32 ± 5.2% in the "poor mobilizers" group of patients (p = 0.002) (Fig. 3BGo).



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  		Figure 3. A) Expression of CXCR4 receptor on mobilized CD34+ cells. Staining and analysis of results were performed as described above for Figure 1Go, except that anti-CD34 antibody (HPCA-2-PE, BD) was matched with anti-CXCR4-FITC (R&D Systems Inc.; Minneapolis, MN). To ensure >100 cells in the double positive quadron, 100,000 cells were collected. Comparison between the three arms of the study is shown for 26 patients. (For details regarding study design, patient population, stem cell mobilization, and stem cell collection [22]). Bone marrow and peripheral blood samples are abbreviated as BM and PB, respectively. d1 to d4 are apheresis collections in four consecutive days. B) Expression of CXCR4 receptor on mobilized CD34+ cells: "good mobilizers" versus "poor mobilizers." The results presented are from the pool of patients in arms A, B, and C as described in (A), but grouped as "good mobilizers" in arms A, B, and C (>=2 x 106 CD34+CD45dim cells/kg), or as "poor mobilizers" (<0.4 x 106 CD34+CD45dim cells/kg, in two consecutive collections). Other details are as in (A).

 
These findings suggest a role for the CXCR4 receptor and the SDF-1 chemokine in holding CD34+ cells in place in the bone marrow. At this point, we did not determine the levels of SDF-1 in bone marrow and apheresis collections in this study, however, since SDF-1 can modulate the expression of its own receptor, CXCR4 [87, 88], we believe that the levels of this chemokine in the bone marrow at steady-state should vary from the levels in the peripheral blood of mobilized patients. More studies are required to determine the exact role of CXCR4 and its chemokine, SDF-1, in the process of mobilization.

In summary, it appears that downregulation of the expression of L-selectin, VLA-4, and CXCR4 are required in the process of release of PBSC from the marrow to the peripheral blood. However, homing of PBSC into the bone marrow and engraftment requires high expression of these molecules on CD34+ cells. Therefore, one must assume that increased expression of VLA-4, L-selectin, and SDF-1 receptor occurs in vivo, following infusion of the PBSC product. Indeed, recent studies suggest that in vitro culturing of PBSC with a variety of hematopoietic growth factors upregulates the expression of VLA-4 and L-selectin [72], and that SDF-1 alone or in combination with other growth factors such as G-CSF or GM-CSF upregulates the expression of CXCR4 [83, 86, 87]. These recent findings begin to explain the molecular mechanisms of stem cell release from the bone marrow to the peripheral blood.


   References
Top
 Abstract
 Introduction
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Received July 11, 2000; accepted for publication August 8, 2000.




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