Thalidomide modulation of the immune response in female B6C3F1 mice: a host resistance study.

Previously, we have reported that thalidomide (Thd) treatment can modulate the immune responses in female B6C3F1 mice. The present study was designed to evaluate whether or not these immunomodulatory responses were of sufficient magnitude to alter host resistances in a number of pathogen and tumor models. B6C3F1 mice were treated intraperitoneally with Thd (30-150 mg/kg) for 14 or 28 days, then inoculated with either Plasmodium yeolii, PYB6 fibrosarcoma tumor cells, B16F10 melanoma tumor cells, Listeria monocytogenes, or Streptococcus pneumoniae. Significant dose-dependent protection against B16F10 and L. monocytogenes was observed in mice that were treated with Thd. Furthermore, time course study using bacterial colony-forming units per spleen and liver as the endpoints indicated that the protective effect of Thd on host resistance to L. monocytogenes was time-dependent. In contrast, Thd treatment did not affect host resistance to P. yeolii, S. pneumoniae and PYB6 tumor. Additionally, the effect of Thd on the phagocytic function of the mononuclear phagocyte system (MPS) was evaluated following intravenous injection of 51Cr-labeled sRBCs. The overall phagocytic activity of MPS was not significantly altered by Thd treatment. In conclusion, these results demonstrate that Thd immunomodulation altered host resistance to B16F10 and L. monocytogenes; and selective modulation of Thd on the immune system may be responsible for the pathogen or tumor-specific effect of this compound.

Differential stimulation of IgE production, STAT activation and cytokine and CD86 expression by 2,4-dinitrochlorobenzene and trimellitic anhydride.

It has been reported that dermal exposure to trimellitic anhydride (TMA, 50%), a respiratory allergen, induced greater production of serum IgE and expression of Th2 cytokines than 2,4-dinitrochlorobenzene (DNCB, 1%), a potent contact sensitizer, in female BALB/C mice. To determine if there is any strain difference, four strains (B6C3F1, C57BL/6, BDF1 and BALB/C) of female mice were employed in this study to compare the differential effects of these chemicals on the hypersensitivity responses. Serum IgE levels were increased in TMA-treated B6C3F1, C57BL/6 and BDF1 mice when compared with the DNCB treatment and vehicle controls; in contrast, no difference was observed between TMA- and DNCB-treated BALB/C mice, although both chemicals induced greater IgE production than vehicle controls. In vitro expression of interleukin 4 (IL-4) and IL-13 mRNA by overnight concanavalin A (ConA)-stimulated draining lymph node cells was enhanced following in vivo treatment with TMA but not with DNCB in the B6C3F1, C57BL/6 and BDF1 mice. In contrast, TMA and DNCB induced similar levels of IL-4 and IL-13 mRNA in the BALB/C mice. The IL-4 protein levels in the supernatants of overnight ConA-treated draining lymph node cells were also increased in TMA-treated B6C3F1 and C57BL/6 mice when compared with the DNCB treatment and vehicle controls. Further mechanistic evaluation in the B6C3F1 mice indicated that the activation of STAT6 but not STAT4 by ConA plus IL-2-treated draining lymph node cells was increased in TMA- but not DNCB-treated mice when compared with the vehicle controls. Furthermore, surface expression of B7.2 (CD86) by B cells was increased in both TMA- and DNCB-treated B6C3F1 mice when compared with the vehicles; however, greater B7.2 expression was observed in TMA-treated compared with DNCB-treated. Overall, these results demonstrate that a similar pattern of IgE and cytokine production was observed in these strains of mice except for BALB/C. Furthermore, differential activation of STAT6 and expression of CD86 following exposure to TMA and DNCB may contribute to the differential production of IgE and cytokines.

Influence of MHC background on the antibody response to detergent enzymes in the mouse intranasal test.

The mouse intranasal test (MINT) was developed to assess the immunogenic potential of detergent enzymes. The BDF1 mouse (H-2(b/d)), a cross of C57Bl/6 (H-2(b)) x DBA/2 (H-2(d)) has been used for most of the development work. Preliminary data in the CB6F1(H-2(d/b)), a cross of Balb/c (H-2(d)) x C57Bl/6 showed that this strain was similar to the BDF1 in its response to enzymes. These data also showed that the parental strains responded differently to the enzymes. To understand better the influence the major histocompatibility complex (MHC) background has on immune responses to enzymes, 3 different enzymes were tested in 4 inbred strains (C57Bl/6, DBA/2, Balb/c, and C57Bl/10), 2 hybrid strains (BDF1 and CB6F1), and 2 congenic strains (Balb.B10 and B10.D2). BDF1 mice rank enzymes the same as the guinea pig, which in turn correlates with sensitization in occupationally exposed humans. The ranking is based upon the dose of enzyme needed to give one-half maximal IgG1 antibody response (ED(50)) where Termamyl is more potent than Alcalase, which is equipotent to Savinase. The H-2(d) strains ranked the enzymes the same as the BDF1 but generated ED(50)s for the proteases that were one order of magnitude greater than the BDF1 ED(50)s. The response to Termamyl was the same in the two F1 strains and the H-2(d) strains. The H-2(b) strains did not rank the enzymes the same as BDF1 but the ED(50)s for the proteases were similar to the ED(50)s in the F1 strains. The response to Termamyl in the H-2(b) strains was lower than the response in the F1 and H-2(d) strains. Initial data show that the inbred strains will make enzyme-specific IgE antibody to high doses of enzyme with DBA/2 > Balb/c > C57Bl/6 in terms of the robustness of the response. The IgG1 responses in the congenic strains were similar to the responses in the H-2 matched strains. In addition, the antibody response to enzymes was consistent regardless of the source of BDF1 mice. The responses to these enzymes are clearly MHC linked with a role for Class II I-E molecules indicated. The current data strongly support the use of the F1 hybrid as an appropriate strain for evaluating allergic responses to enzymes.