CXCL9 and CXCL10 plasma levels: Potential keys to unlocking CLAD risk
Year: 2022
Type: editorial
Abstract: The chemoattractants CXCL9 and CXCL10 are chemokines that bind to the shared receptor CXCR3, potentiating T cells, mononuclear cells, and natural killer (NK) cells. Previous studies demonstrated that presence of these chemokines in BAL samples preceded development of chronic lung allograft dysfunction (CLAD), suggesting their role in the development and prediction of CLAD.1, 2 In this issue, Shino et al.3 hypothesized that plasma levels of CXCL9/CXCL10 may be predictors of CLAD development. They prospectively evaluated plasma samples and histopathological findings of 184 patients at the time of transbronchial biopsies performed during the first year following transplantation, demonstrating a dose–response relationship between plasma levels of CXCL9/CXCL10, histopathological patterns of acute rejection (AR), acute lung injury (ALI), and CLAD risk. Importantly, AR and ALI are known risk factors to the development of CLAD, yet this study found the increased risk was dependent on the presence of CXCL9/CXCL10 plasma elevation. Despite improved understanding of clinical phenotypes and their related prognosis and the development of consensus CLAD definitions,4 effective CLAD treatments are lacking and CLAD remains the primary etiology limiting long-term survival post–lung transplantation. Recurrent epithelial injury causing an inflammatory response and impaired wound healing is a leading hypothesis for the pathogenesis of CLAD. Despite this, attempts at augmenting immunosuppression after CLAD diagnosis have shown no benefit. Therefore, early identification of patients at risk, possibly during the active inflammatory phase, rather than once abnormal wound healing pathways dominate resulting in irreversible injury, provides an attractive opportunity for intervention. Early prediction of CLAD as well as identification of new targets for intervention remain a primary objective for improving outcomes. CLAD prediction research efforts have focused on biomarkers. In fact, the Cystic Fibrosis Foundation recently funded a request for applications focused solely on the development of early detection and diagnosis of CLAD using novel biomarker.5 To date, the “ideal” biomarker—noninvasively obtained, sensitive, and specific for CLAD risk—has yet to be identified. In their work, Shino et al. offer evidence to support the utility of plasma CXCL9/CXCL10 as clinically useful CLAD biomarkers. CXCL9 and CXCL10 are expressed in transplanted organs during AR, leading to directional migration of activated T cells contributing to allograft injury.6 Elevated CXCL9/CXCL10 in BAL samples and plasma prior to CLAD diagnosis support their involvement in CLAD development. BAL fluid biomarkers require bronchoscopy, an invasive procedure with possible complications; therefore, plasma biomarkers provide an attractive alternative. In the current study, patients with histopathological lung injury plus elevated plasma CXCL9/CXCL10 levels predicted increasing CLAD risk—patients with only histologic injury or elevated cytokine levels alone were not at increased risk. Identification of concomitant chemokine plasma elevation and histopathologic injury may provide an opportunity for early intervention with a more aggressive immunosuppression approach. This is of particular relevance in cases of low-grade rejection identified on surveillance biopsies, as no consensus exists regarding treatment versus observation in these cases.7 Furthermore, although azithromycin has been shown to alter the course of lung function decline in some patients and is a recommended treatment in cases of lung function decline prior CLAD diagnosis, the optimal timing of azithromycin therapy for CLAD prevention is unknown. A less invasive plasma marker may guide a more informed decision of the timing of azithromycin initiation. The role of chemoattractants CXCL9/CXCL10 and their shared receptor CXCR3 in the pathogenesis of allograft injury may also provide a possible target for intervention. In animal models, inhibition or deletion of CXCL10 delayed the onset of rejection and prolonged graft survival. Of particular interest is a study of SCH 546738, a CXCR3 antagonist that inhibits CXCL10 and CXCL11 binding, thus preventing activated T-cell chemotaxis. In this study, SCH 546738 alone achieved increased survival of rat cardiac allografts.8 In a murine model of murine cardiac and islet cell transplant, administration of the small-molecule TAK-779, targeting CCR5 and CXCR3, significantly increased survival and decreased the development of chronic vasculopathy.9 Utilizing a combination of histopathology plus plasma CXCL9/CXCL10 levels may serve as a useful means of enriching future clinical trials aimed at evaluating novel CLAD-directed therapeutics as well as designing pragmatic trials aimed at identifying transplant recipients who benefit from augmented immunosuppression or enhanced monitoring. While plasma CXCL9/CXCL10 levels alone may not be the “ideal” CLAD biomarkers given the important interaction between histopathology and plasma cytokine levels and the requirement for tissue to identify the patients at highest CLAD risk, the additive predictive value of plasma CXCL9/CXCL10 may be instrumental in advancing our ability to identify at risk patients and ameliorate CLAD risk. Developing biomarkers offering (1) early detection of CLAD, (2) detection of an increased risk for subsequent CLAD development, and (3) identification of new potential targets for possible intervention studies should continue to be the focus of research aimed at improving long term outcomes in lung transplantation. The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.
DOI: 10.1111/ajt.17135
Authors: Osnat Shtraichman, Joshua M. Diamond
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,300
OpenAlex ID: W4283767429