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Endoplasmic reticulum stress-mediated apoptosis involved in indirect recognition pathway blockade induces long-term heart allograft survival.

Xiang J, Gu X, Qian S, Chen Z - J. Biomed. Biotechnol. (2010)

Bottom Line: This approach could specifically and effectively knock down CD80 and CD86 expression.We also found a higher percentage of apoptotic T cells in lymph tissues and grafts than that detected in control group.Our results indicated that ERS-induced apoptosis may be involved in allogeneic T-cell apoptosis, and the ERS-mediated apoptosis pathway may be a novel target in clinical prevention and therapy of allograft rejection.

View Article: PubMed Central - PubMed

Affiliation: Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China.

ABSTRACT
Implementation of dendritic cell- (DC-) based therapies in organ transplantation can reduce dependency on nonspecific immunosuppression. Despite extensive research, mechanisms of equipped DCs inducing transplant tolerance remain incomplete. Here, we applied RNA interference technique to inhibit CD80 and CD86 expression in host bone marrow-derived DCs. This approach could specifically and effectively knock down CD80 and CD86 expression. T cells primed by these DCs inhibited allogeneic responses. Administration of recipient DCs loaded with alloantigen after CD80 and CD86 blockade prolonged cardiac allograft survival. We also found a higher percentage of apoptotic T cells in lymph tissues and grafts than that detected in control group. In addition, these T cells expressed high expression of GRP78 than controls, indicating activation of unfolded protein responses. Upregulation of CHOP expression among these cells suggested that the endoplasmic reticulum stress (ERS) response switched to a proapoptotic response. Our results indicated that ERS-induced apoptosis may be involved in allogeneic T-cell apoptosis, and the ERS-mediated apoptosis pathway may be a novel target in clinical prevention and therapy of allograft rejection.

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(a) B6 alloAg-pulsed, CD80 lenti- and CD86 lenti-transduced DCs were inferior stimulators of naïve syngeneic C3H T cells, compared to alloAg-pulsed NC lenti-transduced DCs or no treated DCs. *P < .05 compared to NC lenti/No treated. (b) DCs loaded with debris B6 spleen cells were injected into syngeneic C3H mice (3 × 106/mouse). Seven days later, recipients were sacrificed and splenic T cells challenged ex vivo with γ-irradiated C3H DCs pulsed with Ag (BALB/c, C3H, or B6 splenocyte lysates). Data are expressed as cpm ±1SD from triplicate cultures and are representative of four separate experiments.
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fig4: (a) B6 alloAg-pulsed, CD80 lenti- and CD86 lenti-transduced DCs were inferior stimulators of naïve syngeneic C3H T cells, compared to alloAg-pulsed NC lenti-transduced DCs or no treated DCs. *P < .05 compared to NC lenti/No treated. (b) DCs loaded with debris B6 spleen cells were injected into syngeneic C3H mice (3 × 106/mouse). Seven days later, recipients were sacrificed and splenic T cells challenged ex vivo with γ-irradiated C3H DCs pulsed with Ag (BALB/c, C3H, or B6 splenocyte lysates). Data are expressed as cpm ±1SD from triplicate cultures and are representative of four separate experiments.

Mentions: To explore the influence of these DCs on T cell response, DCs were transduced with recombinant lentivirus. After pulsing B6 splenocyte lysates, DCs were used as stimulators of naïve C3H splenic T cells. CD80 lenti and CD86 lenti-transduced DCs were poor stimulators of T cells compared to NC lenti-transduced DCs or no treated DCs (Figure 4(a)). Next, these DCs were injected into C3H mice through the lateral tail vein. As shown in Figure 4(b), T cells from C3H mice primed by injection of CD80 lenti and CD86 lenti-transduced DCs exhibited marked reduced responses to alloAg (B6) versus to third party unrelated Ag (BALB/c) pulsed C3H-derived DCs. In contrast, T cells from C3H mice primed by injection of NC lenti-transduced or no treated DCs exhibited markedly increased proliferative responses to donor alloAg and third party Ag-pulsed C3H-derived DCs. However, T cells from C3H mice primed by injection of various DCs all exhibited significant low proliferative response to syngeneic Ag (C3H) pulsed DCs.


Endoplasmic reticulum stress-mediated apoptosis involved in indirect recognition pathway blockade induces long-term heart allograft survival.

Xiang J, Gu X, Qian S, Chen Z - J. Biomed. Biotechnol. (2010)

(a) B6 alloAg-pulsed, CD80 lenti- and CD86 lenti-transduced DCs were inferior stimulators of naïve syngeneic C3H T cells, compared to alloAg-pulsed NC lenti-transduced DCs or no treated DCs. *P < .05 compared to NC lenti/No treated. (b) DCs loaded with debris B6 spleen cells were injected into syngeneic C3H mice (3 × 106/mouse). Seven days later, recipients were sacrificed and splenic T cells challenged ex vivo with γ-irradiated C3H DCs pulsed with Ag (BALB/c, C3H, or B6 splenocyte lysates). Data are expressed as cpm ±1SD from triplicate cultures and are representative of four separate experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2871569&req=5

fig4: (a) B6 alloAg-pulsed, CD80 lenti- and CD86 lenti-transduced DCs were inferior stimulators of naïve syngeneic C3H T cells, compared to alloAg-pulsed NC lenti-transduced DCs or no treated DCs. *P < .05 compared to NC lenti/No treated. (b) DCs loaded with debris B6 spleen cells were injected into syngeneic C3H mice (3 × 106/mouse). Seven days later, recipients were sacrificed and splenic T cells challenged ex vivo with γ-irradiated C3H DCs pulsed with Ag (BALB/c, C3H, or B6 splenocyte lysates). Data are expressed as cpm ±1SD from triplicate cultures and are representative of four separate experiments.
Mentions: To explore the influence of these DCs on T cell response, DCs were transduced with recombinant lentivirus. After pulsing B6 splenocyte lysates, DCs were used as stimulators of naïve C3H splenic T cells. CD80 lenti and CD86 lenti-transduced DCs were poor stimulators of T cells compared to NC lenti-transduced DCs or no treated DCs (Figure 4(a)). Next, these DCs were injected into C3H mice through the lateral tail vein. As shown in Figure 4(b), T cells from C3H mice primed by injection of CD80 lenti and CD86 lenti-transduced DCs exhibited marked reduced responses to alloAg (B6) versus to third party unrelated Ag (BALB/c) pulsed C3H-derived DCs. In contrast, T cells from C3H mice primed by injection of NC lenti-transduced or no treated DCs exhibited markedly increased proliferative responses to donor alloAg and third party Ag-pulsed C3H-derived DCs. However, T cells from C3H mice primed by injection of various DCs all exhibited significant low proliferative response to syngeneic Ag (C3H) pulsed DCs.

Bottom Line: This approach could specifically and effectively knock down CD80 and CD86 expression.We also found a higher percentage of apoptotic T cells in lymph tissues and grafts than that detected in control group.Our results indicated that ERS-induced apoptosis may be involved in allogeneic T-cell apoptosis, and the ERS-mediated apoptosis pathway may be a novel target in clinical prevention and therapy of allograft rejection.

View Article: PubMed Central - PubMed

Affiliation: Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China.

ABSTRACT
Implementation of dendritic cell- (DC-) based therapies in organ transplantation can reduce dependency on nonspecific immunosuppression. Despite extensive research, mechanisms of equipped DCs inducing transplant tolerance remain incomplete. Here, we applied RNA interference technique to inhibit CD80 and CD86 expression in host bone marrow-derived DCs. This approach could specifically and effectively knock down CD80 and CD86 expression. T cells primed by these DCs inhibited allogeneic responses. Administration of recipient DCs loaded with alloantigen after CD80 and CD86 blockade prolonged cardiac allograft survival. We also found a higher percentage of apoptotic T cells in lymph tissues and grafts than that detected in control group. In addition, these T cells expressed high expression of GRP78 than controls, indicating activation of unfolded protein responses. Upregulation of CHOP expression among these cells suggested that the endoplasmic reticulum stress (ERS) response switched to a proapoptotic response. Our results indicated that ERS-induced apoptosis may be involved in allogeneic T-cell apoptosis, and the ERS-mediated apoptosis pathway may be a novel target in clinical prevention and therapy of allograft rejection.

Show MeSH
Related in: MedlinePlus