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Heterologous immunity triggered by a single, latent virus in Mus musculus: combined costimulation- and adhesion- blockade decrease rejection.

Beus JM, Hashmi SS, Selvaraj SA, Duan D, Stempora LL, Monday SA, Cheeseman JA, Hamby KM, Speck SH, Larsen CP, Kirk AD, Kean LS - PLoS ONE (2013)

Bottom Line: MHV68 infection was correlated with multimodal immune deviation, which included increased secretion of CXCL9 and CXCL10, and with the expansion of a CD8(dim) T cell population.In the setting of MHV68 latency, recipients demonstrated accelerated costimulation blockade-resistant rejection of skin allografts compared to non-infected animals (MST 13.5 d in infected animals vs 22 d in non-infected animals, p<.0001).While in the non-infected cohort, either CTLA-4-Ig or anti-CD154 alone could effectively pair with adhesion blockade to prolong allograft acceptance, in infected animals, the prolonged acceptance of skin grafts could only be recapitulated when anti-LFA-1 and anti-VLA-4 antibodies were combined with anti-CD154 (without CTLA-4-Ig, MST>100 d).

View Article: PubMed Central - PubMed

Affiliation: Emory Transplant Center, Emory University School of Medicine, Atlanta, Georgia, United States of America.

ABSTRACT
The mechanisms underlying latent-virus-mediated heterologous immunity, and subsequent transplant rejection, especially in the setting of T cell costimulation blockade, remain undetermined. To address this, we have utilized MHV68 to develop a rodent model of latent virus-induced heterologous alloimmunity. MHV68 infection was correlated with multimodal immune deviation, which included increased secretion of CXCL9 and CXCL10, and with the expansion of a CD8(dim) T cell population. CD8(dim) T cells exhibited decreased expression of multiple costimulation molecules and increased expression of two adhesion molecules, LFA-1 and VLA-4. In the setting of MHV68 latency, recipients demonstrated accelerated costimulation blockade-resistant rejection of skin allografts compared to non-infected animals (MST 13.5 d in infected animals vs 22 d in non-infected animals, p<.0001). In contrast, the duration of graft acceptance was equivalent between non-infected and infected animals when treated with combined anti-LFA-1/anti-VLA-4 adhesion blockade (MST 24 d for non-infected and 27 d for infected, p = n.s.). The combination of CTLA-4-Ig/anti-CD154-based costimulation blockade+anti-LFA-1/anti-VLA-4-based adhesion blockade led to prolonged graft acceptance in both non-infected and infected cohorts (MST>100 d for both, p<.0001 versus costimulation blockade for either). While in the non-infected cohort, either CTLA-4-Ig or anti-CD154 alone could effectively pair with adhesion blockade to prolong allograft acceptance, in infected animals, the prolonged acceptance of skin grafts could only be recapitulated when anti-LFA-1 and anti-VLA-4 antibodies were combined with anti-CD154 (without CTLA-4-Ig, MST>100 d). Graft acceptance was significantly impaired when CTLA-4-Ig alone (no anti-CD154) was combined with adhesion blockade (MST 41 d). These results suggest that in the setting of MHV68 infection, synergy occurs predominantly between adhesion pathways and CD154-based costimulation, and that combined targeting of both pathways may be required to overcome the increased risk of rejection that occurs in the setting of latent-virus-mediated immune deviation.

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Comparative Effect of CTLA-4-Ig and anti-CD154+ adhesion blockade in MHV68-infected and non-infected mice.A) Kaplan-Meier survival curves comparing skin graft survival between the following groups of MHV68-infected mice: MHV68-infected mice treated with CoB (solid red line, MST 13.5 d, n = 40, 7 independent experiments); MHV68-infected mice treated with anti-LFA-1+ anti-VLA-4 (solid orange line, MST 27 d, n = 14, 2 independent experiments); MHV68-infected mice treated with anti-CD154+ anti-LFA-1/anti-VLA-4 (solid violet line, MST>100 d, n = 8, one experiment); MHV68-infected mice treated with CTLA-4-Ig+anti-LFA-1/anti-VLA-4 (solid magenta line, MST 41 d, n = 8, one experiment); MHV68-infected mice treated with CoB+anti-LFA-1/anti-VLA-4 (solid green line, MST>100 d, n = 25, 3 independent experiments). Skin graft survival between groups was compared using the log-rank test. In infected animals, the combination of anti-LFA-1 and anti-VLA-4 was compared to CoB alone resulting in p = .0023. CTLA-4-Ig+anti-LFA-1/anti-VLA-4 compared to CoB alone yielded p = .0002. The combination of anti-CD154+ anti-LFA-1/anti-VLA-4 was significantly different from CoB alone (p<.0001) and not significantly different from dual CoB (anti-CD154+ CTLA-4-Ig)+dual adhesion blockade (p = .73). B) Kaplan-Meier survival curves comparing skin graft survival between the following groups of non-infected mice: non-infected mice treated with CoB (dotted red line, MST 22 d, n = 48, 8 independent experiments); non-infected mice treated with anti-LFA-1+ anti-VLA-4 (dotted orange line, MST 24, n = 12, 2 independent experiments); non-infected mice treated with anti-CD154+ anti-LFA-1/anti-VLA-4 (dotted violet line, MST>100 d, n = 8, one experiment); non-infected mice treated with CTLA-4-Ig+anti-LFA-1/anti-VLA-4 (dotted magenta line, MST>100 d, n = 8, one experiment); non-infected mice treated with CoB+anti-LFA-1/anti-VLA-4 (dotted green line, MST>100 d, n = 26, 3 independent experiments). Graft survival between groups in non-infected animals was compared with the log-rank method. Survival in the CoB only and anti-LFA-1+ anti-VLA-4 groups was not significantly different (p = .87). Relative to CoB alone, survival was significantly prolonged in non-infected animals treated with anti-CD154+ anti-LFA-1/anti-VLA-4 (p<.0001), CTLA-4-Ig+anti-LFA-1/anti-VLA-4 (p<.0001), or dual CoB (anti-CD154+ CTLA-4-Ig)+anti-LFA-1/anti-VLA-4 (p<.0001).
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pone-0071221-g008: Comparative Effect of CTLA-4-Ig and anti-CD154+ adhesion blockade in MHV68-infected and non-infected mice.A) Kaplan-Meier survival curves comparing skin graft survival between the following groups of MHV68-infected mice: MHV68-infected mice treated with CoB (solid red line, MST 13.5 d, n = 40, 7 independent experiments); MHV68-infected mice treated with anti-LFA-1+ anti-VLA-4 (solid orange line, MST 27 d, n = 14, 2 independent experiments); MHV68-infected mice treated with anti-CD154+ anti-LFA-1/anti-VLA-4 (solid violet line, MST>100 d, n = 8, one experiment); MHV68-infected mice treated with CTLA-4-Ig+anti-LFA-1/anti-VLA-4 (solid magenta line, MST 41 d, n = 8, one experiment); MHV68-infected mice treated with CoB+anti-LFA-1/anti-VLA-4 (solid green line, MST>100 d, n = 25, 3 independent experiments). Skin graft survival between groups was compared using the log-rank test. In infected animals, the combination of anti-LFA-1 and anti-VLA-4 was compared to CoB alone resulting in p = .0023. CTLA-4-Ig+anti-LFA-1/anti-VLA-4 compared to CoB alone yielded p = .0002. The combination of anti-CD154+ anti-LFA-1/anti-VLA-4 was significantly different from CoB alone (p<.0001) and not significantly different from dual CoB (anti-CD154+ CTLA-4-Ig)+dual adhesion blockade (p = .73). B) Kaplan-Meier survival curves comparing skin graft survival between the following groups of non-infected mice: non-infected mice treated with CoB (dotted red line, MST 22 d, n = 48, 8 independent experiments); non-infected mice treated with anti-LFA-1+ anti-VLA-4 (dotted orange line, MST 24, n = 12, 2 independent experiments); non-infected mice treated with anti-CD154+ anti-LFA-1/anti-VLA-4 (dotted violet line, MST>100 d, n = 8, one experiment); non-infected mice treated with CTLA-4-Ig+anti-LFA-1/anti-VLA-4 (dotted magenta line, MST>100 d, n = 8, one experiment); non-infected mice treated with CoB+anti-LFA-1/anti-VLA-4 (dotted green line, MST>100 d, n = 26, 3 independent experiments). Graft survival between groups in non-infected animals was compared with the log-rank method. Survival in the CoB only and anti-LFA-1+ anti-VLA-4 groups was not significantly different (p = .87). Relative to CoB alone, survival was significantly prolonged in non-infected animals treated with anti-CD154+ anti-LFA-1/anti-VLA-4 (p<.0001), CTLA-4-Ig+anti-LFA-1/anti-VLA-4 (p<.0001), or dual CoB (anti-CD154+ CTLA-4-Ig)+anti-LFA-1/anti-VLA-4 (p<.0001).

Mentions: Given the reciprocal balance that was observed between graft acceptance and MHV68 viral load when combined CTLA-4-Ig+anti-CD154 CoB and adhesion blockade were simultaneously employed, we next determined whether a more limited immunomodulatory platform could be designed that was still capable of overcoming MHV68-mediated allograft rejection. As shown in Figure 8A, when CTLA-4-Ig alone (without anti-CD154) was combined with dual adhesion blockade in MHV68-infected animals, allograft survival was significantly shortened compared to when adhesion blockade was combined with both CTLA-4-Ig and anti-CD154 (MST 41 d with CTLA-4-Ig alone and adhesion blockade, p = .024 compared to MST>100 d with combined CoB+adhesion blockade). In contrast, the combination of anti-CD154 (without CTLA-4-Ig) and dual adhesion blockade in infected animals was similarly effective to combined costimulation- and adhesion- blockade in prolonging allograft acceptance. (MST>100 d, p = n.s. compared to combined CoB+adhesion blockade, Figure 8A).


Heterologous immunity triggered by a single, latent virus in Mus musculus: combined costimulation- and adhesion- blockade decrease rejection.

Beus JM, Hashmi SS, Selvaraj SA, Duan D, Stempora LL, Monday SA, Cheeseman JA, Hamby KM, Speck SH, Larsen CP, Kirk AD, Kean LS - PLoS ONE (2013)

Comparative Effect of CTLA-4-Ig and anti-CD154+ adhesion blockade in MHV68-infected and non-infected mice.A) Kaplan-Meier survival curves comparing skin graft survival between the following groups of MHV68-infected mice: MHV68-infected mice treated with CoB (solid red line, MST 13.5 d, n = 40, 7 independent experiments); MHV68-infected mice treated with anti-LFA-1+ anti-VLA-4 (solid orange line, MST 27 d, n = 14, 2 independent experiments); MHV68-infected mice treated with anti-CD154+ anti-LFA-1/anti-VLA-4 (solid violet line, MST>100 d, n = 8, one experiment); MHV68-infected mice treated with CTLA-4-Ig+anti-LFA-1/anti-VLA-4 (solid magenta line, MST 41 d, n = 8, one experiment); MHV68-infected mice treated with CoB+anti-LFA-1/anti-VLA-4 (solid green line, MST>100 d, n = 25, 3 independent experiments). Skin graft survival between groups was compared using the log-rank test. In infected animals, the combination of anti-LFA-1 and anti-VLA-4 was compared to CoB alone resulting in p = .0023. CTLA-4-Ig+anti-LFA-1/anti-VLA-4 compared to CoB alone yielded p = .0002. The combination of anti-CD154+ anti-LFA-1/anti-VLA-4 was significantly different from CoB alone (p<.0001) and not significantly different from dual CoB (anti-CD154+ CTLA-4-Ig)+dual adhesion blockade (p = .73). B) Kaplan-Meier survival curves comparing skin graft survival between the following groups of non-infected mice: non-infected mice treated with CoB (dotted red line, MST 22 d, n = 48, 8 independent experiments); non-infected mice treated with anti-LFA-1+ anti-VLA-4 (dotted orange line, MST 24, n = 12, 2 independent experiments); non-infected mice treated with anti-CD154+ anti-LFA-1/anti-VLA-4 (dotted violet line, MST>100 d, n = 8, one experiment); non-infected mice treated with CTLA-4-Ig+anti-LFA-1/anti-VLA-4 (dotted magenta line, MST>100 d, n = 8, one experiment); non-infected mice treated with CoB+anti-LFA-1/anti-VLA-4 (dotted green line, MST>100 d, n = 26, 3 independent experiments). Graft survival between groups in non-infected animals was compared with the log-rank method. Survival in the CoB only and anti-LFA-1+ anti-VLA-4 groups was not significantly different (p = .87). Relative to CoB alone, survival was significantly prolonged in non-infected animals treated with anti-CD154+ anti-LFA-1/anti-VLA-4 (p<.0001), CTLA-4-Ig+anti-LFA-1/anti-VLA-4 (p<.0001), or dual CoB (anti-CD154+ CTLA-4-Ig)+anti-LFA-1/anti-VLA-4 (p<.0001).
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pone-0071221-g008: Comparative Effect of CTLA-4-Ig and anti-CD154+ adhesion blockade in MHV68-infected and non-infected mice.A) Kaplan-Meier survival curves comparing skin graft survival between the following groups of MHV68-infected mice: MHV68-infected mice treated with CoB (solid red line, MST 13.5 d, n = 40, 7 independent experiments); MHV68-infected mice treated with anti-LFA-1+ anti-VLA-4 (solid orange line, MST 27 d, n = 14, 2 independent experiments); MHV68-infected mice treated with anti-CD154+ anti-LFA-1/anti-VLA-4 (solid violet line, MST>100 d, n = 8, one experiment); MHV68-infected mice treated with CTLA-4-Ig+anti-LFA-1/anti-VLA-4 (solid magenta line, MST 41 d, n = 8, one experiment); MHV68-infected mice treated with CoB+anti-LFA-1/anti-VLA-4 (solid green line, MST>100 d, n = 25, 3 independent experiments). Skin graft survival between groups was compared using the log-rank test. In infected animals, the combination of anti-LFA-1 and anti-VLA-4 was compared to CoB alone resulting in p = .0023. CTLA-4-Ig+anti-LFA-1/anti-VLA-4 compared to CoB alone yielded p = .0002. The combination of anti-CD154+ anti-LFA-1/anti-VLA-4 was significantly different from CoB alone (p<.0001) and not significantly different from dual CoB (anti-CD154+ CTLA-4-Ig)+dual adhesion blockade (p = .73). B) Kaplan-Meier survival curves comparing skin graft survival between the following groups of non-infected mice: non-infected mice treated with CoB (dotted red line, MST 22 d, n = 48, 8 independent experiments); non-infected mice treated with anti-LFA-1+ anti-VLA-4 (dotted orange line, MST 24, n = 12, 2 independent experiments); non-infected mice treated with anti-CD154+ anti-LFA-1/anti-VLA-4 (dotted violet line, MST>100 d, n = 8, one experiment); non-infected mice treated with CTLA-4-Ig+anti-LFA-1/anti-VLA-4 (dotted magenta line, MST>100 d, n = 8, one experiment); non-infected mice treated with CoB+anti-LFA-1/anti-VLA-4 (dotted green line, MST>100 d, n = 26, 3 independent experiments). Graft survival between groups in non-infected animals was compared with the log-rank method. Survival in the CoB only and anti-LFA-1+ anti-VLA-4 groups was not significantly different (p = .87). Relative to CoB alone, survival was significantly prolonged in non-infected animals treated with anti-CD154+ anti-LFA-1/anti-VLA-4 (p<.0001), CTLA-4-Ig+anti-LFA-1/anti-VLA-4 (p<.0001), or dual CoB (anti-CD154+ CTLA-4-Ig)+anti-LFA-1/anti-VLA-4 (p<.0001).
Mentions: Given the reciprocal balance that was observed between graft acceptance and MHV68 viral load when combined CTLA-4-Ig+anti-CD154 CoB and adhesion blockade were simultaneously employed, we next determined whether a more limited immunomodulatory platform could be designed that was still capable of overcoming MHV68-mediated allograft rejection. As shown in Figure 8A, when CTLA-4-Ig alone (without anti-CD154) was combined with dual adhesion blockade in MHV68-infected animals, allograft survival was significantly shortened compared to when adhesion blockade was combined with both CTLA-4-Ig and anti-CD154 (MST 41 d with CTLA-4-Ig alone and adhesion blockade, p = .024 compared to MST>100 d with combined CoB+adhesion blockade). In contrast, the combination of anti-CD154 (without CTLA-4-Ig) and dual adhesion blockade in infected animals was similarly effective to combined costimulation- and adhesion- blockade in prolonging allograft acceptance. (MST>100 d, p = n.s. compared to combined CoB+adhesion blockade, Figure 8A).

Bottom Line: MHV68 infection was correlated with multimodal immune deviation, which included increased secretion of CXCL9 and CXCL10, and with the expansion of a CD8(dim) T cell population.In the setting of MHV68 latency, recipients demonstrated accelerated costimulation blockade-resistant rejection of skin allografts compared to non-infected animals (MST 13.5 d in infected animals vs 22 d in non-infected animals, p<.0001).While in the non-infected cohort, either CTLA-4-Ig or anti-CD154 alone could effectively pair with adhesion blockade to prolong allograft acceptance, in infected animals, the prolonged acceptance of skin grafts could only be recapitulated when anti-LFA-1 and anti-VLA-4 antibodies were combined with anti-CD154 (without CTLA-4-Ig, MST>100 d).

View Article: PubMed Central - PubMed

Affiliation: Emory Transplant Center, Emory University School of Medicine, Atlanta, Georgia, United States of America.

ABSTRACT
The mechanisms underlying latent-virus-mediated heterologous immunity, and subsequent transplant rejection, especially in the setting of T cell costimulation blockade, remain undetermined. To address this, we have utilized MHV68 to develop a rodent model of latent virus-induced heterologous alloimmunity. MHV68 infection was correlated with multimodal immune deviation, which included increased secretion of CXCL9 and CXCL10, and with the expansion of a CD8(dim) T cell population. CD8(dim) T cells exhibited decreased expression of multiple costimulation molecules and increased expression of two adhesion molecules, LFA-1 and VLA-4. In the setting of MHV68 latency, recipients demonstrated accelerated costimulation blockade-resistant rejection of skin allografts compared to non-infected animals (MST 13.5 d in infected animals vs 22 d in non-infected animals, p<.0001). In contrast, the duration of graft acceptance was equivalent between non-infected and infected animals when treated with combined anti-LFA-1/anti-VLA-4 adhesion blockade (MST 24 d for non-infected and 27 d for infected, p = n.s.). The combination of CTLA-4-Ig/anti-CD154-based costimulation blockade+anti-LFA-1/anti-VLA-4-based adhesion blockade led to prolonged graft acceptance in both non-infected and infected cohorts (MST>100 d for both, p<.0001 versus costimulation blockade for either). While in the non-infected cohort, either CTLA-4-Ig or anti-CD154 alone could effectively pair with adhesion blockade to prolong allograft acceptance, in infected animals, the prolonged acceptance of skin grafts could only be recapitulated when anti-LFA-1 and anti-VLA-4 antibodies were combined with anti-CD154 (without CTLA-4-Ig, MST>100 d). Graft acceptance was significantly impaired when CTLA-4-Ig alone (no anti-CD154) was combined with adhesion blockade (MST 41 d). These results suggest that in the setting of MHV68 infection, synergy occurs predominantly between adhesion pathways and CD154-based costimulation, and that combined targeting of both pathways may be required to overcome the increased risk of rejection that occurs in the setting of latent-virus-mediated immune deviation.

Show MeSH
Related in: MedlinePlus