Donor CD4 T Cells Trigger Costimulation Blockade-Resistant Donor Bone Marrow Rejection through Bystander Activation Requiring Interleukin 6
Division of Transplantation, Department of Surgery, Medical University of Vienna, Vienna, Austria
Meeting: 2013 American Transplant Congress
Abstract number: 385
Background:
Donor T cells have pleiotropic effects in allogeneic bone marrow transplantation (BMT). Co-transplanting high doses of donor T cells with donor BM causes rejection of donor BM despite costimulation-blockade. In the present study we investigate the molecular mechanisms responsible for this seemingly paradoxical phenomenon.
Methods:
Recipients (C57BL/6) were treated with 3Gy TBI and received approximately 20×106 unseparated Balb/c BMC and costimulation-blockers (anti-CD154mAb, CTLA4Ig). 30×106 CD4 T cells (MACS isolation) from Balb/c, CB6F1 (Balb/cxB6), irradiated Balb/c, C3H or B6 were co-transplanted. Groups either received anti-IL-6, anti-IFN-y, anti-LFA1mAb or rapamycin. Multilineage chimerism was followed by flow cytometry and cytokine release was analyzed.
Results:
Co-transplantation of 30×106 CD4 T cells but not CD8 T cells triggered rapid BM rejection of donor BM under costimulation-blockade within one week in an otherwise successful protocol (0/13 vs 17/20 chimeras, p<0.001). The levels of IL-6, IFN-y and IL-17A (p<0.05) were found to be higher in mice treated with additional donor T cells. The neutralization of IL-6, but not of IFN-y abrogate the detrimental effect of donor T cells (5/7 vs 0/5 chimeras; p<0.05). The injection of CB6F1, irradiated Balb/c and recipient (B6) CD4 T cells induced chimerism (5/6, 4/5 and 6/6 vs. 0/4 chimeras with Balb/c T cells; p<0.05) whereas C3H CD4 T cells led to BM rejection (0/5 vs 9/9 chimeras BMT, p<0,001). The additional treatment with rapamycin or anti-LFA1 overcame the negative effect of donor T cell injection (5/5 and 6/6 vs 0/4 chimeras; p<0.01).
Conclusion:
Injected T cells need to recognize the recipient as allogeneic but do not need to be recognized as allogeneic by the recipient in order to trigger rejection of donor bone marrow. This bystander activation induced rejection requires IL-6 and can be prevented by rapamycin or anti-LFA1, which are potential therapeutic interventions for treatment of costimulation blockade-resistant rejection.
To cite this abstract in AMA style:
Hock K, Pilat N, Baranyi U, Mahr B, Klaus C, Gattringer M, Wekerle T. Donor CD4 T Cells Trigger Costimulation Blockade-Resistant Donor Bone Marrow Rejection through Bystander Activation Requiring Interleukin 6 [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/donor-cd4-t-cells-trigger-costimulation-blockade-resistant-donor-bone-marrow-rejection-through-bystander-activation-requiring-interleukin-6/. Accessed May 17, 2025.« Back to 2013 American Transplant Congress