Complement system in lung transplantation

Ali, Hakim Azfar; Pavlisko, Elizabeth N.; Snyder, Laurie D.; Frank, Michael M.; Palmer, Scott M.

doi:10.1111/ctr.13208

Cited by 21 publications

(20 citation statements)

References 66 publications

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“…While the role of complement activation in acute lung injury has been evaluated in both experimental ( 16 ) and clinical settings ( 25 , 26 ), its role in lung allograft injury is only beginning to be explored ( 27 , 28 ). While targeting the complement cascade has been successful in certain preclinical models ( 29 – 31 ), follow-up studies have been met with tempered enthusiasm, despite moderate success in clinical trials ( 20 , 32 ).…”

Section: Discussionmentioning

confidence: 99%

Local complement activation is associated with primary graft dysfunction after lung transplantation

Kulkarni

Ramphal

et al. 2020

JCI Insight

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Bronchoalveolar lavage (BAL) and plasma specimens were obtained from recipients within 24 hours after LTx. PGD was scored based on the consensus definition. Complement activation products and components of each arm of the complement cascade were measured using ELISA. RESULTS. In both cohorts, sC4d and sC5b-9 levels were increased in BAL of subjects with PGD compared with those without PGD. Subjects with PGD also had higher C1q, C2, C4, and C4b, compared with subjects without PGD, suggesting classical and lectin pathway involvement. Ba levels were higher in subjects with PGD, suggesting alternative pathway activation. Among lectin pathway-specific components, MBL and FCN-3 had a moderate-to-strong correlation with the terminal complement complex in the BAL but not in the plasma. CONCLUSION. Complement activation fragments are detected in the BAL within 24 hours after LTx. Components of all 3 pathways are locally increased in subjects with PGD. Our findings create a precedent for investigating complement-targeted therapeutics to mitigate PGD.

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Section: Discussionmentioning

confidence: 99%

Local complement activation is associated with primary graft dysfunction after lung transplantation

Kulkarni

Ramphal

et al. 2020

JCI Insight

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“…Our results suggest that C3(H 2 O) increases in the BAL fluid of lung transplant recipients prior to the development AMR. While complement activation has been connected with AMR (46, 47, 49), C4d staining in lung of AMR patients is neither sensitive nor specific, and an entity of C4d-negative AMR is also increasingly appreciated (48). Moreover, C4d staining needs a biopsy to be performed, and is most likely to be positive around the time of AMR diagnosis.…”

Section: Discussionmentioning

confidence: 99%

Development and Optimization of an ELISA to Quantitate C3(H2O) as a Marker of Human Disease

Elvington

Liszewski

et al. 2019

Front. Immunol.

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Discovery of a C3(H 2 O) uptake pathway has led to renewed interest in this alternative pathway triggering form of C3 in human biospecimens. Previously, a quantifiable method to measure C3(H 2 O), not confounded by other complement activation products, was unavailable. Herein, we describe a sensitive and specific ELISA for C3(H 2 O). We initially utilized this assay to determine baseline C3(H 2 O) levels in healthy human fluids and to define optimal sample storage and handling conditions. We detected ~500 ng/ml of C3(H 2 O) in fresh serum and plasma, a value substantially lower than what was predicted based on previous studies with purified C3 preparations. After a single freeze-thaw cycle, the C3(H 2 O) concentration increased 3- to 4-fold (~2,000 ng/ml). Subsequent freeze-thaw cycles had a lesser impact on C3(H 2 O) generation. Further, we found that storage of human sera or plasma samples at 4°C for up to 22 h did not generate additional C3(H 2 O). To determine the potential use of C3(H 2 O) as a biomarker, we evaluated specimens from patients with inflammatory-driven diseases. C3(H 2 O) concentrations were moderately increased (1.5- to 2-fold) at baseline in sera from active systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) patients compared to healthy controls. In addition, upon challenge with multiple freeze-thaw cycles or incubation at 22 or 37°C, C3(H 2 O) generation was significantly enhanced in SLE and RA patients' sera. In bronchoalveolar lavage fluid from lung-transplant recipients, we noted a substantial increase in C3(H 2 O) within 3 months of acute antibody-mediated rejection. In conclusion, we have established an ELISA for assessing C3(H 2 O) as a diagnostic and prognostic biomarker in human diseases.

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“…In the last few years, targeted SNP analyses focused on the role of the complement system in solid organ transplantation have increased (4, 39, 40). Our group previously reported a genetic promoter polymorphism in several complement regulatory proteins to be associated with chronic rejection after LTx (41), and with kidney transplant outcome (42).…”

Section: Discussionmentioning

confidence: 99%

“…In solid organ transplantation, complement proteins play an important role in both acute, and chronic rejection (4). In a prospective cohort study it was shown that increased levels of complement proteins C4a and C5a early after LTx were associated with primary graft dysfunction (5).…”

Section: Introductionmentioning

confidence: 99%

A Single Nucleotide C3 Polymorphism Associates With Clinical Outcome After Lung Transplantation

et al. 2019

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Background: Development of chronic rejection is still a severe problem and causes high mortality rates after lung transplantation (LTx). Complement activation is important in the development of acute rejection (AR) and bronchiolitis obliterans syndrome, with C3 as a key complement factor.Methods: We investigated a single nucleotide polymorphism (SNP) in the C3 gene (rs2230199) in relation to long-term outcome after LTx in 144 patient-donor pairs. In addition, we looked at local production of donor C3 by analyzing bronchoalveolar lavage fluid (BALF) of 6 LTx patients using isoelectric focusing (IEF).Results: We demonstrated the presence of C3 in BALF and showed that this is produced by the donor lung based on the genotype of SNP rs2230199. We also analyzed donor and patient SNP configurations and observed a significant association between the SNP configuration in patients and episodes of AR during 4-years follow-up. Survival analysis showed a lower AR-free survival in homozygous C3 slow patients (p = 0.005). Furthermore, we found a significant association between the SNP configuration in donors and BOS development. Patients receiving a graft from a donor with at least one C3 fast variant for rs2230199 had an inferior BOS-free survival (p = 0.044).Conclusions: In conclusion, our data indicate local C3 production by donor lung cells. In addition, a single C3 SNP present in recipients affects short-term outcome after LTx, while this SNP in donors has an opposite effect on long-term outcome after LTx. These results could contribute to an improved risk stratification after transplantation.

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Complement system in lung transplantation

Cited by 21 publications

References 66 publications

Local complement activation is associated with primary graft dysfunction after lung transplantation

Local complement activation is associated with primary graft dysfunction after lung transplantation

Development and Optimization of an ELISA to Quantitate C3(H2O) as a Marker of Human Disease

A Single Nucleotide C3 Polymorphism Associates With Clinical Outcome After Lung Transplantation

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