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Hsp90 inhibition ameliorates CD4 + T cell ‐ mediated acute Graft versus Host disease in mice

View Article: PubMed Central - PubMed

ABSTRACT

Introduction: For many patients with leukemia only allogeneic bone marrow transplantion provides a chance of cure. Co‐transplanted mature donor T cells mediate the desired Graft versus Tumor (GvT) effect required to destroy residual leukemic cells. The donor T cells very often, however, also attack healthy tissue of the patient inducing acute Graft versus Host Disease (aGvHD)—a potentially life‐threatening complication.

Methods: Therefore, we used the well established C57BL/6 into BALB/c mouse aGvHD model to evaluate whether pharmacological inhibition of heat shock protein 90 (Hsp90) would protect the mice from aGvHD.

Results: Treatment of the BALB/c recipient mice from day 0 to +2 after allogeneic CD4+ T cell transplantation with the Hsp90 inhibitor 17‐(dimethylaminoethylamino)‐17‐demethoxygeldanamycin (DMAG) partially protected the mice from aGvHD. DMAG treatment was, however, insufficient to prolong overall survival of leukemia‐bearing mice after transplantation of allogeneic CD4+ and CD8+ T cells. Ex vivo analyses and in vitro experiments revealed that DMAG primarily inhibits conventional CD4+ T cells with a relative resistance of CD4+ regulatory and CD8+ T cells toward Hsp90 inhibition.

Conclusions: Our data, thus, suggest that Hsp90 inhibition might constitute a novel approach to reduce aGvHD in patients without abrogating the desired GvT effect.

No MeSH data available.


Related in: MedlinePlus

aGvHD induced by CD4+ and CD8+ T cells is resistant to DMAG‐mediated Hsp90 inhibition in vivo. Lethally irradiated BALB/c mice were reconstituted with 107 C57BL/6 TCD BM cells either alone (n = 2) or together with 5 × 105 (A, C) (DMAG n = 7, DMSO n = 8) or 5 × 104 (B, C) donor T cells (n = 8). After TCD BM and total CD4+ and CD8+ T cell transfer, mice were again treated as in the experiments depicted in Figure 1. (A, B) The percentages of animals surviving over time are depicted. (C) Contribution of different causes of death (lymphoma, aGvHD, not analyzed) to overall lethality. Lymphoma burden was determined by measuring frequencies and absolute numbers of BCL1 cells in spleens of recipient mice post mortem (n = 4–8). Data from two individual experiments were pooled.
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iid3127-fig-0003: aGvHD induced by CD4+ and CD8+ T cells is resistant to DMAG‐mediated Hsp90 inhibition in vivo. Lethally irradiated BALB/c mice were reconstituted with 107 C57BL/6 TCD BM cells either alone (n = 2) or together with 5 × 105 (A, C) (DMAG n = 7, DMSO n = 8) or 5 × 104 (B, C) donor T cells (n = 8). After TCD BM and total CD4+ and CD8+ T cell transfer, mice were again treated as in the experiments depicted in Figure 1. (A, B) The percentages of animals surviving over time are depicted. (C) Contribution of different causes of death (lymphoma, aGvHD, not analyzed) to overall lethality. Lymphoma burden was determined by measuring frequencies and absolute numbers of BCL1 cells in spleens of recipient mice post mortem (n = 4–8). Data from two individual experiments were pooled.

Mentions: To determine whether Hsp90 inhibition by DMAG would also protect from aGvHD induced by total CD4+ and CD8+ T cells and to assess its impact on the GvT effect, we inoculated BALB/c mice with BCL1 lymphoma cells followed by transplantation of either TCD BM cells only or TCD BM cells together with 5 × 105 (Fig. 3A, C) or 5 × 104 T cells/mouse (Fig. 3B, C). The recipient mice were then treated with DMAG or DMSO as described above. In contrast to CD4+ T cell‐induced aGvHD, survival (Fig. 3A, B) and clinical scoring (Suppl. Fig. S1E, SF) during the first 20 days after transplantation of total T cells suggested that DMAG treatment had no protective effect under these conditions regardless of the amount of total T cells transplanted. After day 20 the mice receiving TCD BM cells only showed signs of advanced BCL1 lymphoma with, however, no improvement of survival after DMAG treatment. Transplantation of 5 × 105 T cells even worsened overall survival as these mice succumb to aGvHD earlier than the mice suffering from the BCL1 lymphoma (Fig. 3A, C). Recipients of 5 × 104 T cells showed better survival than all other groups of mice, but still, with one exception in the DMSO group, all mice died by day 50 post transplantation (Fig. 3B) from either aGvHD or the BCL1 lymphoma (Fig. 3C). The frequencies of aGvHD‐ versus BCL1 lymphoma‐related lethality were equally high in mice receiving DMAG or DMSO (Fig. 3C). Therefore, DMAG treatment did not ameliorate aGvHD induced by CD4+ and CD8+ T cells, but also did not negatively interfere with the GvT effect.


Hsp90 inhibition ameliorates CD4 + T cell ‐ mediated acute Graft versus Host disease in mice
aGvHD induced by CD4+ and CD8+ T cells is resistant to DMAG‐mediated Hsp90 inhibition in vivo. Lethally irradiated BALB/c mice were reconstituted with 107 C57BL/6 TCD BM cells either alone (n = 2) or together with 5 × 105 (A, C) (DMAG n = 7, DMSO n = 8) or 5 × 104 (B, C) donor T cells (n = 8). After TCD BM and total CD4+ and CD8+ T cell transfer, mice were again treated as in the experiments depicted in Figure 1. (A, B) The percentages of animals surviving over time are depicted. (C) Contribution of different causes of death (lymphoma, aGvHD, not analyzed) to overall lethality. Lymphoma burden was determined by measuring frequencies and absolute numbers of BCL1 cells in spleens of recipient mice post mortem (n = 4–8). Data from two individual experiments were pooled.
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iid3127-fig-0003: aGvHD induced by CD4+ and CD8+ T cells is resistant to DMAG‐mediated Hsp90 inhibition in vivo. Lethally irradiated BALB/c mice were reconstituted with 107 C57BL/6 TCD BM cells either alone (n = 2) or together with 5 × 105 (A, C) (DMAG n = 7, DMSO n = 8) or 5 × 104 (B, C) donor T cells (n = 8). After TCD BM and total CD4+ and CD8+ T cell transfer, mice were again treated as in the experiments depicted in Figure 1. (A, B) The percentages of animals surviving over time are depicted. (C) Contribution of different causes of death (lymphoma, aGvHD, not analyzed) to overall lethality. Lymphoma burden was determined by measuring frequencies and absolute numbers of BCL1 cells in spleens of recipient mice post mortem (n = 4–8). Data from two individual experiments were pooled.
Mentions: To determine whether Hsp90 inhibition by DMAG would also protect from aGvHD induced by total CD4+ and CD8+ T cells and to assess its impact on the GvT effect, we inoculated BALB/c mice with BCL1 lymphoma cells followed by transplantation of either TCD BM cells only or TCD BM cells together with 5 × 105 (Fig. 3A, C) or 5 × 104 T cells/mouse (Fig. 3B, C). The recipient mice were then treated with DMAG or DMSO as described above. In contrast to CD4+ T cell‐induced aGvHD, survival (Fig. 3A, B) and clinical scoring (Suppl. Fig. S1E, SF) during the first 20 days after transplantation of total T cells suggested that DMAG treatment had no protective effect under these conditions regardless of the amount of total T cells transplanted. After day 20 the mice receiving TCD BM cells only showed signs of advanced BCL1 lymphoma with, however, no improvement of survival after DMAG treatment. Transplantation of 5 × 105 T cells even worsened overall survival as these mice succumb to aGvHD earlier than the mice suffering from the BCL1 lymphoma (Fig. 3A, C). Recipients of 5 × 104 T cells showed better survival than all other groups of mice, but still, with one exception in the DMSO group, all mice died by day 50 post transplantation (Fig. 3B) from either aGvHD or the BCL1 lymphoma (Fig. 3C). The frequencies of aGvHD‐ versus BCL1 lymphoma‐related lethality were equally high in mice receiving DMAG or DMSO (Fig. 3C). Therefore, DMAG treatment did not ameliorate aGvHD induced by CD4+ and CD8+ T cells, but also did not negatively interfere with the GvT effect.

View Article: PubMed Central - PubMed

ABSTRACT

Introduction: For many patients with leukemia only allogeneic bone marrow transplantion provides a chance of cure. Co‐transplanted mature donor T cells mediate the desired Graft versus Tumor (GvT) effect required to destroy residual leukemic cells. The donor T cells very often, however, also attack healthy tissue of the patient inducing acute Graft versus Host Disease (aGvHD)—a potentially life‐threatening complication.

Methods: Therefore, we used the well established C57BL/6 into BALB/c mouse aGvHD model to evaluate whether pharmacological inhibition of heat shock protein 90 (Hsp90) would protect the mice from aGvHD.

Results: Treatment of the BALB/c recipient mice from day 0 to +2 after allogeneic CD4+ T cell transplantation with the Hsp90 inhibitor 17‐(dimethylaminoethylamino)‐17‐demethoxygeldanamycin (DMAG) partially protected the mice from aGvHD. DMAG treatment was, however, insufficient to prolong overall survival of leukemia‐bearing mice after transplantation of allogeneic CD4+ and CD8+ T cells. Ex vivo analyses and in vitro experiments revealed that DMAG primarily inhibits conventional CD4+ T cells with a relative resistance of CD4+ regulatory and CD8+ T cells toward Hsp90 inhibition.

Conclusions: Our data, thus, suggest that Hsp90 inhibition might constitute a novel approach to reduce aGvHD in patients without abrogating the desired GvT effect.

No MeSH data available.


Related in: MedlinePlus