IL-6 Promotes Cardiac Graft Rejection Mediated by CD4+ Cells

Abstract

IL-6 mediates numerous immunologic effects relevant to transplant rejection; however its specific contributions to these processes are not fully understood. To this end, we neutralized IL-6 in settings of acute cardiac allograft rejection associated with either CD8+ or CD4+ cell dominant responses. In a setting of CD8+ cell dominant graft rejection, IL-6 neutralization delayed the onset of acute rejection while decreasing graft infiltrate and inverting anti-graft Th1/Th2 priming dominance in recipients. IL-6 neutralization markedly prolonged graft survival in the setting of CD4+ cell mediated acute rejection and was associated with decreased graft infiltrate, altered Th1 responses, and reduced serum alloantibody. Further, in CD4+ cell dominated rejection, IL-6 neutralization was effective when anti-IL-6 administration was delayed by as many as six days post-transplant. Finally, IL-6 deficient graft recipients were protected from CD4+ cell dominant responses suggesting that IL-6 production by graft recipients, rather than grafts, is necessary for this type of rejection. Cumulatively, these observations define IL-6 as a critical promoter of graft infiltration and a shaper of T cell lineage development in cardiac graft rejection. In light of these findings, the utility of therapeutics targeting IL-6 should be considered for preventing cardiac allograft rejection.

RNA Profiling in Human and Murine Transplanted Hearts: Identification and Validation of Therapeutic Targets for Acute Cardiac and Renal Allograft Rejection

“…The comparison of significantly dysregulated transcripts in transplanted mice and patients manifesting rejection yielded 70 common dysregulated mRNAs, with 33 of these 70 coding for proteins involved in the IL‐6 pathway. These findings are in line with previous reports on the role of IL‐6 in cardiac rejection 40, 41 and urge for further efforts to determine the true potential of IL‐6 targeting to prevent ACR. Importantly, the pro‐inflammatory effects of miR‐155 during ACR implicate that it targets mRNAs coding for anti‐inflammatory proteins.…”

Allogeneic Mesenchymal Stromal Cells Transplanted Onto the Heart Surface Achieve Therapeutic Myocardial Repair Despite Immunologic Responses in Rats

“…Quantitative reverse transcription polymerase chain reaction revealed that myocardial expression of IL‐6 was upregulated in the allo group compared with the auto group (Figure 7A). IL‐6 has been reported to be involved in promoting allograft rejection 15, 16. Serum IL‐6 levels, however, were unchanged at the minimum detectable levels between groups (Figure 7B).…”

Anti-Interleukin-6 Promotes Allogeneic Bone Marrow Engraftment and Prolonged Graft Survival in an Irradiation-Free Murine Transplant Model

“…Indicated recipients were additionally treated with an anti-IL-6 mAb (1 mg on days −1, 1, and 3 and then 0.1 mg every other day until day 13, MP5-20F3, BioXcell) (27, 28). Where indicated, groups of mice received in addition (0.5 mg on days −1, 1, and 3 and 0.1 mg every other day until day 13) anti-IL-6R (15A7) or anti-IL-17A (BZN035, Novartis Pharma AG) (42, 43).…”