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Clin Exp Immunol. Jun 1998; 112(3): 495–500.
PMCID: PMC1904992

Deoxyspergualin preferentially inhibits the growth and maturation of anti-CD40-activated surface IgD+ B lymphocytes


Deoxyspergualin (DSG), an analogue of spermidin, is a potent immunosuppressive drug with an action quite distinct from that of cyclosporin, rapamycin, or FK506. In this study we investigated the effect of DSG and methyldeoxyspergualin (MeDSG) on the proliferation and differentiation of human B cells stimulated with anti-CD40 MoAb. Highly purified B cells obtained from tonsillar samples were used as target cells. Both agents inhibited the proliferative response of anti-CD40-stimulated B cells in the absence and presence of IL-4, IL-2 or IL-10 in a dose-dependent manner. This inhibitory effect differed markedly among cell populations based on surface IgD expression: strong inhibition of sIgD+ B cells but little inhibition of sIgD B cells. The drugs also suppressed the production of IgG, IgM and IgA by unfractionated B cells, which suggests that DSG acts against post-switch (sIgD) B cells. Although the drugs suppressed immunoglobulin synthesis by both sIgD+ and sIgD B cells, the effect was more marked in the sIgD+ B cells. Analysis of the subclass of IgG secreted by slgD+ B cells revealed a decline in IgG1 and IgG3 in the presence of DSG. These results suggest that DSG preferentially inhibits the growth and maturation of sIgD+ naive B cells.

Keywords: human, B lymphocytes, cellular differentiation, cellular proliferation, immunomodulators


Deoxyspergualin (DSG), a novel immunosuppressive agent, is a synthetic analogue of the bacterial metabolite spergualin produced by Bacillus laterosporus [1]. This drug is unrelated to other immunosuppressive agents, including FK506, cyclosporin A and rapamycin. DSG displays strong immunosuppressive activity in animal models, prolonging survival of allografts and xenografts [2,3]. In humans, the drug has been shown to reverse kidney and liver graft rejection [4,5].

The immunosuppressive activities of DSG are attributed to suppression of both humoral and cell-mediated immune response. DSG has a variety of effects, including inhibition of antigen processing in monocytes [6], modulation of IL-1 production and MHC class II antigen [79], and inhibition of lymphocyte differentiation at pre-T and pre-B cell stages [10]. Though DSG cannot inhibit T cell proliferation stimulated with polyclonal mitogens [5], it can suppress the antibody response to both T cell-dependent antigens, such as keyhole limpet haemocyanin (KLH), sheep erythrocytes, anti-CD3 and immunotoxin, and T cell-independent antigens, such as dinitrophenylated lipopolysacchride (DNP–LPS) and DNP–Ficoll [11]. The above results suggest that DSG acts against B cells and monocytes.

DSG has been shown to bind specifically to heat shock protein 70 (hsp70) [12,13]. Hsp70 is involved in immunoregulatory pathways. The variety of functions exhibited by hsp suggests they are a new class of immunophilin. Although hsp70 is a cellular binding protein for DSG, its action is not directly altered by DSG [14]. Therefore, a role for hsp70 as a target of DSG action remains to be defined.

We and others have reported that DSG potently immunosuppresses the differentiation of human B lymphocytes [15,16]. A recent study has shown that DSG inhibits the differentiation of murine pre-B cells to mature B cells by blocking κ L chain expression [14]. Thus, the cellular target for DSG action may be B cells at a certain stage of maturation. T cell-dependent and T cell-independent models of B cell activation can be achieved by the stimulation with immunoglobulin cross-linking or Staphylococcus aureus Cowan strain I (SAC) stimulation and anti-CD40 activation, respectively [1719]. In the T cell-dependent model, polyclonal activation and sustained proliferation of human B cells is obtained by presentation of an anti-CD40 MoAb on irradiated mouse L cells stably expressing CDw32/FcRII [19]. Although CD40-mediated stimulation alone dose not induce B cells to differentiate into antibody-producing cells, costimulation with cytokines does.

In our previous study, DSG inhibited the maturation of human B cells into antibody-producing cells in a T cell-independent pathway [16]. Here, we examined the action of DSG on B cells in a T cell-dependent activation pathway using CD40. We conclude that DSG acts on the growth and maturation of human naive B cells.



DSG (1-amino-19-guanidino-11-hydroxy-4,9,12-triazanon-adecane-10,13-dione) and methyldeoxyspergualin (MeDSG; 1-amino-19-guanidino-11-methoxy-4,4,12-triazanonadecane-10,13-dione) were provided by Nippon Kayaku Co. Ltd (Tokyo, Japan). Spergualins were dissolved in physiological saline, sterilized by Millipore filtration, and diluted to the appropriate concentration with the medium. Recombinant human IL-4 and IL-10 were obtained from Genzyme (Cambridge, MA) and R&D Systems (Minneapolis, MN), respectively. Recombinant human IL-2 was a kind gift from Shionogi Pharmaceutical Co. (Osaka, Japan). The CD32/FcRII-transfected Ltk cell line (CDw32L cells) was obtained from American Type Culture Collection (Rockville, MD).


MoAbs for CD40 and PE-conjugated MoAb to CD38 were purchased from PharMingen (San Diego, CA). The FITC-conjugated F(ab′)2 fragment of rabbit anti-mouse immunoglobulin and anti-human IgD MoAb (Dako-IgD26) were obtained from Zymed (San Francisco, CA) and Dako A/S (Glostrup, Denmark), respectively.

Cell preparation

Human tonsils were obtained by tonsillectomy from juvenile patients with chronic tonsillitis and were dispersed into a single-cell suspension. Mononuclear cells were isolated on Ficoll–Hypaque density gradients. Monocytes and natural killer (NK) cells were depleted by incubation with 5 mml-leucine methyl ester (Sigma, St Louis, MO) in a serum-free medium for 45 min. T cells were removed by rosetting twice with 2-aminoethylisothiouronium-bromide (Sigma)-treated sheep erythrocytes (E). Non-rosetted (E) cells were additionally purified by isolating B cells from the interface at 50/65% of a discontinuous Percoll density gradient (Pharmacia, Uppsala, Sweden) for the purpose of collecting a resting B cell fraction. The purity of the isolated B cell preparation exceeded 95% CD19+ cells, with < 0.1% CD3+ or CD16+ cells as measured by flow cytometry.

Cultures in CD40-L cell system

The culture medium consisted of serum-free medium, S-clone SF-H (Sanko Pure Chemical Co. Ltd, Tokyo, Japan) supplemented with streptomycin 100 μg/ml and penicillin G 100 U/ml. In this study we used serum-free culture medium, as fetal calf serum (FCS) contains polyamine oxidase that can hydrolyse DSG to toxic aldehydes [11]. Proliferation assays were performed in 96-well flat-bottomed microtitre plates in 200 μ1 of culture medium in which 0.5 × 104 CDw32L cells previously treated with mitomycin-C (MMC) at a concentration of 50 μg/ml for 30 min were added. B cells (0.5 × 105) were then seeded to cultures. Cells were pulsed with 1 μCi 3H-TdR for the last 18 h of the 7-day culture period. For differentiation assay, 1 × 105 B cells/well were cultured on 1 × 104 MMC-treated CDw32L cells in a final culture volume of 0.2 ml. Supernatants were harvested after 14 days and immunoglobulin levels were determined by ELISA as described elsewhere [16]. ELISA specific for IgG subclasses was evaluated with human IgG subclass combiEIA kit (The Binding Site, Birmingham, UK).

Separation of IgD+ and IgD B cells

Purified IgD+ and IgD subpopulations of B cells were prepared as follows. High-density B cells were incubated with anti-IgD MoAb on ice for 30 min, then washed twice with medium. Magnetic beads coated with sheep anti-mouse IgG (Dynal AS, Oslo, Norway) were added to the stained cells and incubated on ice for 30 min. IgD cells were purified by removing cells bound to the beads with Dynamagnet. Bead-bounded IgD+ cells were vigorously vortexed and then incubated at 37°C for 1 h to remove the immunobeads. The purity of both populations was assessed by flow cytometric analysis on a FACScan.


DSG and MeDSG inhibit the proliferation of anti-CD40 stimulated B cells

To elucidate whether DSG influences the proliferative response of human B cells in a T cell-dependent activation pathway, purified resting B cells were cultured on CDw32L cells with 1 μg/ml anti-CD40 MoAb with or without IL-10 (100 ng/ml), IL-2 (500 U/ml) or IL-4 (500 U/ml) for 7 days. Two spergualins, DSG and MeDSG, were tested in parallel for their effects at concentrations of 0.2–200 μg/ml on the proliferative response of B cells in the CD40 system. 3H-TdR uptake was measured at day 8. Both drugs inhibited the proliferative response of anti-CD40 stimulated B lymphocytes in a dose-dependent manner (Fig. 1). The inhibitory effect of the drugs was also observed in the presence of cytokines including IL-10, IL-2 and IL-4 (Fig. 1). The percentage inhibition varied among cultures, ranging from 48% to 85% at a concentration of 200 μg/ml. The results in Fig. 1 are representative of four independent experiments performed under the same conditions.

Fig. 1
Effects of deoxyspergualin (DSG) and methyldeoxyspergualin (MeDSG) on the proliferative response of anti-CD40-activated B lymphocytes. Purified B cells (0.5 × 105) were seeded on 0.5 × 104 mitomycin-C (MMC)-treated CDw32L cells with 1 ...

Kinetic studies on the inhibitory effect of DSG on B cell proliferation

For the kinetic study, DSG or MeDSG were added at different time intervals over a 7-day culture period. As shown in Fig. 2, the drugs showed maximal inhibitory effect when present throughout the 7-day culture period. The inhibitory effects declined time-dependently. When added at day 3 of culture, maximal inhibition declined by > 50% and by day 6 the drugs were relatively ineffective. The drugs required several days to mediate their effects on the B cell proliferation, which supports previous findings in murine models [14]. Thus, DSG may act on B cells at the early maturational stage.

Fig. 2
Effects of deoxyspergualin (DSG) and methyldeoxyspergualin (MeDSG) on proliferation when added at various intervals after initiation of cultures. Highly purified B cells were cultured for 7 days in the presence of IL-10 (100 ng/ml) in the CD40 system. ...

DSG preferentially inhibits the proliferative response of surface lgD+ B cells

B cell activation by either the cross-linking of surface immunoglobulin or CD40 ligation involves alternative signal pathways and results in different B cell phenotypes [17]. In the CD40 system, surface IgD (sIgD)+ B cells preferentially proliferate and constitute the long-term proliferating B cell pool ([20], our observation). In contrast, the loss of sIgD (sIgD) accompanies the early stages of B cell activation in immunoglobulin cross-linking or SAC stimulation ([21], our observation). These findings suggest that sIgD+ B cells are a direct target for DSG action in the CD40 system. Therefore, the effect of DSG (200 μg/ml) on the proliferation of sIgD+and sIgD B cells in the CD40 system was investigated in the presence and absence of various cytokines including IL-10, IL-2 and IL-4. sIgD and sIgD+ B cells were isolated with anti-IgD MoAb and immunobeads as described in Materials and Methods. A similar technical approach was used to study naive B cell function [22].

Results in Fig. 3 are representative of one out of four separate experiments. DSG selectively suppressed the proliferative response of sIgD+ B cells but not that of sIgD B cells in a 7-day culture period. The results clearly show that DSG blocked the growth of sIgD+ naive B cells.

Fig. 3
Effect of deoxyspergualin (DSG) on the proliferative responses of sIgD+ and sIgD B cells in the presence or absence of cytokines. sIgD+ and sIgD B cells separated by immunobeads as described in Materials and Methods were cultured (0.5 ...

Effect of the drugs on immunoglobulin generation by B cells

In the CD40 system, IL-10 may be involved in the final step of B cell maturation, as supported by the observation that IL-10 can drive human B cells to a plasma-like stage of differentiation [18]. The effects of DSG and MeDSG on immunoglobulin generation by B cells was examined in the presence of IL-10 (100 ng/ml) during a 14-day culture period. The high-density B cells were induced for immunoglobulin synthesis in the presence and absence of the drugs at concentrations of 0.2–200 μg/ml.

Although activated B cells produce large amounts of immunoglobulins in response to IL-10 in the CD40 system [18], immunoglobulin synthesis in our experimental model was smaller than expected in all four independent experiments. DSG and MeDSG suppressed the antibody secretion of three isotypes, IgG, IgM and IgA (Fig. 4). These results suggest that the drugs affected the post-switch (sIgD) B cells. sIgD B cells were a very minor population at the beginning of the culture, because high-density (resting) B cells were used as target cells in this study. However, sIgD B cells can be generated in vitro from sIgD+ B cells and mature into post-switch B cells during culture in the CD40 system [20]. Therefore, the above results are understandable with the interpretation that DSG acts on sIgD B cells originating from sIgD+ B cells to inhibit immunoglobulin synthesis. To investigate whether sIgD+ B cells are really a target for DSG, the following experiment was undertaken.

Fig. 4
Effects of deoxyspergualin (DSG) and methyldeoxyspergualin (MeDSG) on immunoglobulin synthesis by anti-CD40 stimulated B cells. Purified B cells (1 × 105) were cultured on 1 × 104 mitomycin-C (MMC)-treated CDw32L cells with 1 μg/ml ...

Effect of the drugs on immunoglobulin synthesis by slgD+ and sIgD B cells

Cross-linking of CD40, but not sIg, provided the signal required for induction of not only proliferation but also immunoglobulin synthesis by naive B cells in response to IL-10 [22]. The stimulatory effects of IL-10 in IgM, IgG and IgA synthesis by sIgD and sIgD+ B cells have been identified in the CD40 system [18,23]. In this study, sIgD+ and sIgD B cells were isolated from the high-density B cell component and cultured for 14 days in the presence of IL-10 in the CD40 system. DSG and MeDSG were added (200 μg/ml) at the beginning of the culture period.

Although the capacity of both B cell populations to generate immunoglobulin was small compared with previous reports [18,23], the pattern of immunoglobulin isotypes secreted by the two populations was consistent with previous observations [17,23], in which IgM and IgG was the predominant isotype secreted by sIgD+ and sIgD B cells, respectively. DSG and MeDSG inhibited the synthesis of IgG and IgM secreted by both populations, although the effect was stronger in sIgD+ B cells (Fig. 5). These results suggest that the drugs inhibit immunoglobulin synthesis of both sIgD+ and sIgD B cells.

Fig. 5
sIgD+ and sIgD B cells (1 × 105 cells/well) were incubated in the presence of IL-10 (100 ng/m1) and anti-CD40 MoAb (1 μg/ml). Deoxyspergualin DSG or methyldeoxyspergualin (MeDSG) (200 μg/ml) were added at the initiation ...

Effect of DSG on the IgG subclass pattern generated by slgD+ B cells

Naive B cells exclusively synthesize IgG1 and IgG3 in response to IL-10 [22]. We examined whether the isolated sIgD+ B cells synthesized the characteristic pattern of IgG subclass and DSG interfered with immunoglobulin synthesis. As shown in Fig. 6, sIgD+ B cells secreted IgG1 and IgG3, but little IgG2. DSG inhibited IgG1 and IgG3 synthesis by the sIgD+ B cells in a dose-dependent manner at concentrations of 0.2–200 μg/ml. These results indicate that it is unlikely that the difference in the proliferation and antibody secretion of sIgD+ and sIgD B cells is the result of the isolation procedure.

Fig. 6
sIgD+ B cells (1 × 105 cells/ml) were incubated in the presence of IL-10 (100 ng/m1) and anti-CD40 MoAb (1 μg/ml) with or without deoxyspergualin (DSG) (0.2–200 μg/ml). Supernatants were harvested on day 14 for the measurement ...


In the present study we used the CD40 system to investigate the effect of DSG on the B cells in a T cell-dependent activation pathway.

Antibodies to CD40 have been shown to be directly mitogenic for B cells and support the long-term growth of a non-transformed B cell line when immobilized on the surface of FcRII-bearing fibroblasts [19]. Addition of lymphokines to the cultures induces differentiation, isotype switching, and antibody secretion [18,19,24,25]. In vitro antigen-specific antibody synthesis requires the presence of antigen and IL-10, and activation via CD40 [24]. CD40 is necessary to drive naive B cells into the memory pathway [25]. These findings indicate that the combination of anti-CD40 and cytokines provides both cognate and non-cognate stimulating signals, which substitute for T cell help to B cells.

DSG inhibited the proliferation of anti-CD40-stimulated B cells in a dose-dependent manner (Fig. 1). By contrast, our previous study has demonstrated that DSG scarcely inhibits SAC-stimulated B cell proliferation [16]. Signal pathways induced by T-independent (SAC) and T-dependent (CD40) activation of B cells differ [17]. T-dependent activation does not require sIg cross-linking and the sIg response appears to be protein kinase C (PKC)-dependent and protein kinase A (PKA)-independent, while the CD40 response is PKC-independent [17]. Members of a single population of B cells display different phenotypes and enter alternative differentiation pathways as a result of the response to the different intracellular signals in T-dependent and T-independent pathways [17]. We showed that DSG exhibited discrete action on the B cells in the distinct activation pathways. In contrast, cyclosporin A inhibited antibody production by B cells in response to T-independent but not T-dependent antigen [17].

The kinetic study indicated that exposure to the drugs at the early stage of B cell activation resulted in the blocking of B cell proliferation (Fig. 2). Therefore, DSG seems to act on B cells at a certain stage of maturation.

In the CD40 system, naive B cells can maintain their sIgD expression after entry into the cell cycle, and some B cells acquire advanced isotypes after long-term culture. In fact, sIgD+ B cells preferentially proliferate and thereafter lose the sIgD expression as a consequence of isotype switching [20]. These findings encouraged us to examine the effect of the drug on the proliferation and immunoglobulin synthesis of sIgD+ and sIgD B cell populations. sIgD+ and sIgD cells isolated from tonsillar high-density B cells proliferated in the absence of the drug. DSG remarkably blocked the proliferation of sIgD+ B cells, but had little effect on sIgD B cells (Fig. 3). These results suggest that DSG acts on the naive B cells. However, the drug inhibited the generation of IgG, IgM and IgA by unseparated B cells in a dose-dependent manner in the CD40 system (Fig. 4). Suppression of IgA, IgG and IgM reflects that the drug blocked immunoglobulin synthesis by isotype-committed post-switch (sIgD) B cells. sIgD cells can be generated from sIgD+ B cells and mature during short-term culture in the CD40 activation pathway [19]. Therefore, we examined the effect of DSG on immunoglobulin synthesis by sIgD+ and sIgD B cells. DSG suppressed IgG and IgM synthesis of both populations, although the inhibitory effect was greatest in sIgD+ B cells (Fig. 5). Furthermore, we examined the subclass of IgG secreted by anti-CD40 activated sIgD+ B cells in response to IL-10 in the presence or absence of DSG. sIgD+ naive B cells are induced to secrete IgG1 and IgG3 but not IgG2 or IgG4. In contrast, sIgD isotype-committed B cells produce IgG1, IgG2 and IgG3 when activated through CD40 in the presence of IL-10 [22]. As shown in Fig. 6, mainly IgGl and IgG3 were secreted in the culture of sIgD+ B cells. These results are consistent with a previous report [22]. The amounts of IgG1 and IgG3 were specifically decreased in the presence of DSG. A very small amount of IgG2 detected in the supernatants was not decreased in the presence of DSG in culture.

In the present study, sIgD+ B cells consistently secreted less immunoglobulin than sIgD B cells. This may be due to the use of serum-free culture medium. Additionally, the source of the target B cells, the high-density resting B cell component, may be responsible for the low responsiveness.

The present study indicates that DSG influences the immunoglobulin synthesis of not only naive (sIgD+) B cells, but also post-switch (sIgD) B cells. The finding that DSG suppressed immunoglobulin synthesis by post-switch (sIgD) B cells corresponds with results obtained in a T cell-independent activation pathway [16]. One major point which emerged from this study was that DSG inhibited the growth and immunoglobulin synthesis of sIgD+ naive B cells, although molecular analysis is required to determine the mechanism involved.

Naive B cells that co-express sIgM and sIgD migrate from bone marrow to the periphery and form primary follicles in secondary lymphoid organs. After antigen stimulation, primary follicles develop into secondary follicles, schematically composed of two major microanatomical structures: the mantle zone, in which naive B cells are located, and the germinal centre, in which the antigen-dependent maturation process occurs [26]. Antigen-specific cells that migrate from the germinal centre do not express sIgD. sIgD B cells are functionally active as memory cells, and have undergone somatic hypermutation [27]. As a consequence of the suppression of proliferative response, DSG may influence the development of naive B cells into memory B cells.

The precise mechanism by which DSG immunosuppresses the naive B cells is unknown, but DSG may block the translocation of RelB/NF-κB transcription factor activated by anti-CD40 stimulation. CD40, LPS and anti-immunoglobulin triggering of B cells results in the activation of Rel/NF-κB factors which are involved in the control of a number of genes in lymphoid cells [28]. However, CD40 alone can exert a long-lasting stimulatory effect on both the transcription and nuclear translocation of RelB, while LPS and anti-immunoglobulin are unable to do so [29]. A blockade of the transcriptional activation of κ L chain expression in murine pre-B cells occurs as a result of the blocking of NF-κ B nuclear translocation by DSG [14]. These findings may help to explain the mechanism by which DSG inhibits naive B cell function.

Transplantation of immunocompetent cells from bone marrow or other sources ordinarily leads to an autoimmune reaction and clinical signs of graft-versus-host disease (GVHD) [30]. The effect of DSG at the naive B cell level seems to take advantage of the blockade of the autoimmune system. In fact, DSG is very effective in the prevention and treatment of autoimmune reaction in animal models [31]. The efficacy appears to be attributable to the innate effect of DSG on the naive B cell function.

The mechanism by which DSG affects B cell function seems to be unique among the several immunosuppressive agents reported to date. Cyclosporin A and FK506 exhibit potent immunosuppressive activity by blocking T cell activation. DSG acts at a distinct point in the T–B interaction. Thus, combination treatment of DSG and other immunosuppressants including cyclosporin A and FK506 is considered to be effective.


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