Lung Transplantation

Christie, Jason D.; Van Raemdonck, Dirk; Fisher, Andrew J.

doi:10.1056/nejmra2401039

N Engl J Med

2024

DOI: 10.1056/nejmra2401039

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Lung Transplantation

Jason D. Christie,

Dirk Van Raemdonck,

Andrew J. Fisher

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2024

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Cited by 1 publication

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Impaired complement regulation drives chronic lung allograft dysfunction after lung transplantation

Kulkarni,

Tague,

Calabrese

et al. 2024

Preprint

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A greater understanding of chronic lung allograft dysfunction (CLAD) pathobiology, the primary cause of mortality after lung transplantation, is needed to improve outcomes. The complement system links innate to adaptive immune responses and is activated early post-lung transplantation to form the C3 convertase, a critical enzyme that cleaves the central complement component C3. We hypothesized that LTx recipients with a genetic predisposition to enhanced complement activation have worse CLAD-free survival mediated through increased adaptive alloimmunity. We interrogated a known functional C3 polymorphism (C3R102G) that increases complement activation through impaired C3 convertase inactivation in two independent LTx recipient cohorts. C3R102G, identified in at least one out of three LTx recipients, was associated with worse CLAD-free survival, particularly in the subset of recipients who developed donor-specific antibodies (DSA). In a mouse orthotopic lung transplantation model, impaired recipient complement regulation resulted in more severe obstructive airway lesions when compared to wildtype controls, despite only moderate differences in graft-infiltrating effector T cells. Impaired complement regulation promoted the intragraft accumulation of memory B cells and antibody-secreting cells, resulting in increased DSA levels. In summary, genetic predisposition to complement activation is associated with B cell activation and worse CLAD-free survival.

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Impaired complement regulation drives chronic lung allograft dysfunction after lung transplantation

Kulkarni,

Tague,

Calabrese

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

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Lung Transplantation

Cited by 1 publication

References 74 publications

Impaired complement regulation drives chronic lung allograft dysfunction after lung transplantation

Impaired complement regulation drives chronic lung allograft dysfunction after lung transplantation

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