Airway Oscillometry Detects Spirometric-Silent Episodes of Acute Cellular Rejection.

Rationale: Acute cellular rejection (ACR) is common during the initial 3 months after lung transplant. Patients are monitored with spirometry and routine surveillance transbronchial biopsies. However, many centers monitor patients with spirometry only because of the risks and insensitivity of transbronchial biopsy for detecting ACR. Airway oscillometry is a lung function test that detects peripheral airway inhomogeneity with greater sensitivity than spirometry. Little is known about the role of oscillometry in patient monitoring after a transplant.Objectives: To characterize oscillometry measurements in biopsy-proven clinically significant (grade ≥2 ACR) in the first 3 months after a transplant.Methods: We enrolled 156 of the 209 double lung transplant recipients between December 2017 and March 2019. Weekly outpatient oscillometry and spirometry and surveillance biopsies at Weeks 6 and 12 were conducted at our center.Measurements and Main Results: Of the 138 patients followed for 3 or more months, 15 patients had 16 episodes of grade 2 ACR (AR2) and 44 patients had 64 episodes of grade 0 ACR (AR0) rejection associated with stable and/or improving spirometry. In 15/16 episodes of AR2, spirometry was stable or improving in the weeks leading to transbronchial biopsy. However, oscillometry was markedly abnormal and significantly different from AR0 (P < 0.05), particularly in integrated area of reactance and the resistance between 5 and 19 Hz, the indices of peripheral airway obstruction. By 2 weeks after biopsy, after treatment for AR2, oscillometry in the AR2 group improved and was similar to the AR0 group.Conclusions: Oscillometry identified physiological changes associated with AR2 that were not discernible by spirometry and is useful for graft monitoring after a lung transplant.

A Synthetic Cross-Species CD200R1 Agonist Suppresses Inflammatory Immune Responses In Vivo.

Functional aptamers displaying agonistic or antagonistic properties are showing great promise as modulators of immune responses. Here, we report the development of a polyethylene glycol-modified (PEGylated) DNA aptamer as a cross-species (murine and human) CD200R1 agonist that modulates inflammatory responses in vivo. Specifically, DNA aptamers were discovered by performing independent SELEX searches on recombinant murine and human CD200R1. Aptamer motifs identified by next generation sequencing (NGS) were subsequently compared, leading to the discovery of motifs common to both targets. The CD200R1 DNA aptamer CCS13 displayed the highest agonistic activity toward CD200R1 in terms of suppressing the induction of cytotoxic T-lymphocytes (CTLs) in both human and murine allogeneic-mixed lymphocyte cultures (allo-MLCs). A 20-kDa polyethylene glycol (PEG) chain was covalently attached to the 5' end of this aptamer, and the resulting conjugate was shown to block inflammatory responses in murine models of skin graft rejection and house-dust-mite-induced allergic airway inflammation. Importantly, this agonistic aptamer does not suppress CTL induction in 5-day allo-MLCs with responder cells derived from CD200R1-/- mice, indicating that its mode of action is directly linked to CD200R1 activation. This study suggests that one can derive agonistic DNA aptamers that can be verified as immuno-modulators in murine models with outcomes potentially translatable to the treatment of human conditions.