Cumulative Exposure to Gamma Interferon-Dependent Chemokines CXCL9 and CXCL10 Correlates with Worse Outcome After Lung Transplant

Neujahr, David C.; Perez, Sebastian D.; Mohammed, A.; Ulukpo, Onome; Lawrence, E. Clinton; Fernández, Félix G.; Pickens, Allan; Force, Seth D.; Song, Mingqing; Larsen, Christian; Kirk, Allan D.

doi:10.1111/j.1600-6143.2011.03857.x

Cited by 25 publications

(31 citation statements)

References 21 publications

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“…iMV may also trigger pulmonary and systemic inflammatory responses, 27,28 and increased exposure to chemokines and other inflammatory mediators has been shown to affect both acute rejection 29 and long-term graft survival. 30 …”

Section: Discussionmentioning

confidence: 99%

Spontaneously Breathing Extracorporeal Membrane Oxygenation Support Provides the Optimal Bridge to Lung Transplantation

Schechter

Ganapathi²,

Englum³

et al. 2016

Transplantation

101

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Background Extracorporeal membrane oxygenation (ECMO) is being increasingly used as a bridge to lung transplantation. Small, single-institution series have described increased success using ECMO in spontaneously breathing patients compared with patients on ECMO with mechanical ventilation, but this strategy has not been evaluated on a large scale. Methods Using the United Network for Organ Sharing database, all adult patients undergoing isolated lung transplantation from May 2005 through September 2013 were identified. Patients were categorized by their type of pretransplant support: no support, ECMO only, invasive mechanical ventilation (iMV) only, and ECMO + iMV. Kaplan-Meier survival analysis with log-rank testing was performed to compare survival based on type of preoperative support. A Cox regression model was used to determine whether type of preoperative support was independently associated with survival, using previously established predictors of survival as covariates. Results Approximately 12,403 primary adult pulmonary transplantations were included in this analysis. Sixty-five patients (0.52%) were on ECMO only, 612 (4.93%) required only iMV, 119 (0.96%) were on ECMO + iMV, and the remaining 11,607 (94.6%) required no invasive support before transplantation. One-year survival was decreased in all patients requiring support, regardless of type. However, mid-term survival was similar between patients on ECMO alone and those not on support but significantly worse with patients requiring iMV only or ECMO + iMV. In multivariable analysis, ECMO + iMV and iMV alone were independently associated with decreased survival compared with nonsupport patients, whereas ECMO alone was not significant. Conclusions In patients with worsening pulmonary disease awaiting lung transplantation, those supported via ECMO with spontaneous breathing demonstrated improved survival compared with other bridging strategies.

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Section: Discussionmentioning

confidence: 99%

Spontaneously Breathing Extracorporeal Membrane Oxygenation Support Provides the Optimal Bridge to Lung Transplantation

Schechter

Ganapathi²,

Englum³

et al. 2016

Transplantation

101

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“…Clinical studies evaluating BAL fluid levels CXCL10 (IP-10) in ACR in LTRs have been contradictory (6, 7). Although highly specific, CXCL10 (IP-10) has relatively poor sensitivity for ACR (Figure 4).…”

Section: Discussionmentioning

confidence: 99%

Elevated CXCL10 (IP-10) in Bronchoalveolar Lavage Fluid Is Associated With Acute Cellular Rejection After Human Lung Transplantation

et al. 2014

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Background CXCL10 (IP-10) is a potent chemoattractant for T cells that has been postulated to play arole in infection and acute cellular rejection (ACR) in animal models. We measured CXCL10 (IP-10) (and other cytokines previously implicated in the pathogenesis of ACR) in the bronchoalveolar lavage (BAL) of lung transplant recipients (LTRs) to determine the association between CXCL10 (IP-10) and ACR in LTRs. Methods In a prospective study of 85 LTRs, expression of cytokines (TNF, IFNγ, IL-6, IL-8, IL-15, IL-16, IL-17, CXCL10 (IP-10) and MCP-1 (CCL2)) in BAL samples (n=233) from patients with episodes of ACR (n=44), infection (Infect) (n=25), concomitant ‘Infect +ACR’ (n=10), and ‘No Infect & No ACR’ (n=154) were analyzed. Results The levels of both CXCL10 (IP-10) and IL-16 were significantly increased in histologically proven ACR, as compared to the ‘No Infect & No ACR’ group (CXCL10 [IP-10]: 107.0 vs. 31.9 pg/mL [p=0.001]; IL-16: 472.1 vs. 283.01 [p=0.01]).However, in a linear mixed effects model, significant association was found only between CXCL10 (IP-10)] and ACR. A 1-log increase of CXCL10 (IP-10) was associated with a 40% higher risk of ACR (OR 1.4; 95% CI 1.12-1.84). Conclusion Higher values of CXCL10 (IP-10) in BAL fluid are associated with ACR in LTRs suggesting a potential mechanistic role in the pathogenesis of ACR in LTRs. These results suggest that therapeutic strategies to inhibit CXCL10 (IP-10) and or its cognate receptor, CXCR3, warrant investigation to prevent and/or treat ACR in clinical lung transplantation.

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“…Many analytes (listed in Table S1) where either undetectable in the plasma or exhibited similar levels for both infected and non-infected animals (not shown). In contrast, significant increases in the levels of the chemokines CXCL9 (MIG) and CXCL10 (IP-10), previously demonstrated to play key roles in the trafficking of lymphocytes to sites of inflammation [24], [25] and known to be associated with clinical allograft rejection [26], [27], were observed in infected animals relative to non-infected mice at 2, 4, and 6 weeks after infection (Figure 2). As shown in Figure 2, the median CXCL9 concentration in the serum increased from 105 pg/mL to 755 pg/mL, 1110 pg/mL, and 521 pg/mL at 2, 4, and 6 weeks post-infection, respectively (p<.001, <.001, and <.05, respectively, compared to non-infected controls).…”

Section: Resultsmentioning

confidence: 91%

“…The increased secretion of CXCL9 and CXCL10 is notable, given the critical roles that these molecules may play in both alloreactivity and protective immunity: While the receptor for these ligands, CXCR3, plays a role in protective immunity against MHV68 [49], this axis has also been implicated in the pathogenicity of alloimmunity to murine skin, cardiac, and islet allografts as well as human lung and renal transplants [25]-[27], [50]. We additionally found a correlation of the expansion of a CD8 dim T cell subpopulation with latent MHV68 viral infection.…”

Section: Discussionmentioning

confidence: 99%

Heterologous Immunity Triggered by a Single, Latent Virus in Mus musculus: Combined Costimulation- and Adhesion- Blockade Decrease Rejection

et al. 2013

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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 CD8dim T cell population. CD8dim 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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Cumulative Exposure to Gamma Interferon-Dependent Chemokines CXCL9 and CXCL10 Correlates with Worse Outcome After Lung Transplant

Cited by 25 publications

References 21 publications

Spontaneously Breathing Extracorporeal Membrane Oxygenation Support Provides the Optimal Bridge to Lung Transplantation

Spontaneously Breathing Extracorporeal Membrane Oxygenation Support Provides the Optimal Bridge to Lung Transplantation

Elevated CXCL10 (IP-10) in Bronchoalveolar Lavage Fluid Is Associated With Acute Cellular Rejection After Human Lung Transplantation

Heterologous Immunity Triggered by a Single, Latent Virus in Mus musculus: Combined Costimulation- and Adhesion- Blockade Decrease Rejection

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