Figure 1
Allo-BMT recipients treated with VIP antagonist or transplanted with VIP-KO donors had improved survival following mCMV infection. B10BR and CB6 F1 mice were transplanted with grafts from either VIP-KO or WT C57BL/6 mice. Transplant recipients were treated with 7 daily s.c. injections of 10 μg of VIPhyb or PBS starting the day prior to mCMV infection on day 8 or on day 35 posttransplant. Mice were examined daily for survival and clinical signs of GVHD. Peripheral blood was collected and tetramer+ CD8+ T-cells analyzed by flow cytometry. Viral loads in the liver from mice subjected to necropsy at predetermined time points were measured by plaque assay as previously described.8,14,15 (A-C) Survival of B6→B10BR recipients of 5 × 106 TCD-BM alone or TCD-BM plus 0.1 × 106, 0.3 × 106, or 1 × 106 splenic T-cells, treated with VIPhyb (A) or PBS (B, C). Mice were infected with 1 × 105 mCMV PFU on day 35 posttransplant. Data are pooled from 2 replicate experiments with 12 total mice per group. (D-F) GVHD clinical scores for the B6→B10BR groups transplanted in panels A-C.23-25 (G-I) tetramer+ CD8+ T-cells in the B6→B10BR groups transplanted in panels A-C. (J) Survival of B6→CB6 F1 recipients of 5 × 106 TCD-BM plus 3 × 106 splenocytes following infection with 5 × 103 mCMV PFU on day 8 posttransplantation. Data are from 3 independent experiments with a total of n = 22 mice for each group. (K) GVHD clinical scores in mCMV-infected B6→ CB6 F1 transplant recipients in panel J (SD were +/− 18% of mean values at respective time-points and omitted). (L) tetramer+ CD8+ T-cells in the B6→CB6 F1 groups transplanted in panel J. (M) Survival of B6→CB6 F1 recipients of 5 × 106 TCD-BM plus 3 × 106 splenocytes following 2 × 104 mCMV PFU infection on day 35 posttransplant. Data are pooled from 3 independent experiments; n = 36 for both the WT group and VIP-KO group, and n = 30 for the VIPhyb group. (N) GVHD clinical scores of B6→CB6 F1 transplanted mice from M (SD were +/− 20% of mean values at respective time-points and omitted). (O) Viral load in the liver of B6→CB6 F1 recipients of 5 × 106 TCD-BM plus 3 × 106 splenocytes following infection with 2 × 104 mCMV PFU on day 35 posttransplant. Data in panel O are mean values ± standard error of the mean from 2 replicate experiments with 10 mice per time point. **P < .01 and ***P < .001 signify significant differences between VIP-KO or VIPhyb-treated group and PBS-treated WT group. NS, not significant.

Allo-BMT recipients treated with VIP antagonist or transplanted with VIP-KO donors had improved survival following mCMV infection. B10BR and CB6 F1 mice were transplanted with grafts from either VIP-KO or WT C57BL/6 mice. Transplant recipients were treated with 7 daily s.c. injections of 10 μg of VIPhyb or PBS starting the day prior to mCMV infection on day 8 or on day 35 posttransplant. Mice were examined daily for survival and clinical signs of GVHD. Peripheral blood was collected and tetramer+ CD8+ T-cells analyzed by flow cytometry. Viral loads in the liver from mice subjected to necropsy at predetermined time points were measured by plaque assay as previously described.8,14,15  (A-C) Survival of B6→B10BR recipients of 5 × 106 TCD-BM alone or TCD-BM plus 0.1 × 106, 0.3 × 106, or 1 × 106 splenic T-cells, treated with VIPhyb (A) or PBS (B, C). Mice were infected with 1 × 105 mCMV PFU on day 35 posttransplant. Data are pooled from 2 replicate experiments with 12 total mice per group. (D-F) GVHD clinical scores for the B6→B10BR groups transplanted in panels A-C.23-25  (G-I) tetramer+ CD8+ T-cells in the B6→B10BR groups transplanted in panels A-C. (J) Survival of B6→CB6 F1 recipients of 5 × 106 TCD-BM plus 3 × 106 splenocytes following infection with 5 × 103 mCMV PFU on day 8 posttransplantation. Data are from 3 independent experiments with a total of n = 22 mice for each group. (K) GVHD clinical scores in mCMV-infected B6→ CB6 F1 transplant recipients in panel J (SD were +/− 18% of mean values at respective time-points and omitted). (L) tetramer+ CD8+ T-cells in the B6→CB6 F1 groups transplanted in panel J. (M) Survival of B6→CB6 F1 recipients of 5 × 106 TCD-BM plus 3 × 106 splenocytes following 2 × 104 mCMV PFU infection on day 35 posttransplant. Data are pooled from 3 independent experiments; n = 36 for both the WT group and VIP-KO group, and n = 30 for the VIPhyb group. (N) GVHD clinical scores of B6→CB6 F1 transplanted mice from M (SD were +/− 20% of mean values at respective time-points and omitted). (O) Viral load in the liver of B6→CB6 F1 recipients of 5 × 106 TCD-BM plus 3 × 106 splenocytes following infection with 2 × 104 mCMV PFU on day 35 posttransplant. Data in panel O are mean values ± standard error of the mean from 2 replicate experiments with 10 mice per time point. **P < .01 and ***P < .001 signify significant differences between VIP-KO or VIPhyb-treated group and PBS-treated WT group. NS, not significant.

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