Background: Our previous results demonstrated that both complement fixing (cfABS) as well as non-complement fixing antibodies (ncAbs) to MHC class I result in obliterative airway disease (OAD) in a mouse model following intrabronchial anti-MHC administration. The aim of this study was to test if cfABS and ncAbs at sub threshold levels can synergize and lead to OAD.
Methods: Low dose anti-MHC class I ncAbs mouse IgG1 (100Μg) or cfAbs IgG2a (25Μg) were administered alone or in combination intrabronchially in F1 C57Bl/6 x B.10 mice. Same dose of F(ab)2 fragments of Abs in combination or alone were also administered. Isotype IgGs were used as control. Lungs were analyzed by histopathology. Development of Abs to lung associated self-antigens Kalpha1Tubulin (KΑ1T) and collagenV (ColV) were analyzed by ELISA. Frequency of IFNΓ, IL17, IL-4 and IL10 cells specific to KΑ1T and ColV were enumerated by ELISPOT. Cytokines and growth factor expression were determined by RTPCR.
Results: At sub threshold dose, neither ncAbs (100Μg) nor cfAbs (25Μg) alone led to OAD. However, a combination of ncAbs and cfAbs at the same dose resulted in OAD with C4d deposition in the lungs. In contrast, F(ab)2 portions of Abs alone or in combination did not lead to OAD or C4d deposition. Mice given low dose of complete ncAbs and cfAbs developed serum Abs to KΑ1T (p=0.02) and ColV (p=0.03) compared to ncAbs alone, cfAbs alone or F(ab)2 administered mice. This was associated with increased IFNΓ(p=0.002), IL17 (p=0.004), IL-4 (p<0.05) and suppression of IL-10 (p=0.03) specific to KΑ1T and ColV and upregulation of TNF-Α, VEGF, IL-1Β, IL-6 and TGF-Β.
Conclusions: Both ncAbs and cfAbs to MHC (200ug) lead to OAD, but sub threshold doses of ncAbs or cfAbs given alone did not induce OAD. However, sub threshold levels of ncAbs and cfAbs in combination, can synergize resulting in activation of inflammatory and fibrotic cascades leading to OAD. This effect was dependent on the Fc-portion of Abs, as F(ab)2 preparations of either Abs did not lead to OAD. Hence, we postulate that multiple low titers of de novo developed DSA detected as low MFI by Luminex following transplantation can synergize leading to chronic lung allograft rejection.
To cite this abstract in AMA style:Subramanian V, Takenaka M, Tiriveedhi V, Gelman A, Patterson G, Mohanakumar T. Synergism of Complement-Fixing and Non-Complement-Fixing Antibodies to MHC Class I in Pathogenesis of Obliterative Airway Disease: Obligatory Role for the Fc Portion of Immunoglobulins [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/synergism-of-complement-fixing-and-non-complement-fixing-antibodies-to-mhc-class-i-in-pathogenesis-of-obliterative-airway-disease-obligatory-role-for-the-fc-portion-of-immunoglobulins/. Accessed November 23, 2020.
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