Date: Sunday, May 3, 2015
Session Time: 5:30pm-6:30pm
Presentation Time: 5:30pm-6:30pm
Location: Exhibit Hall E
Bone marrow (BM)-derived MSC given the day before kidney allografts localize into lymphoid organs and induce significant prolongation of graft survival in mice. By contrast, MSC given post-transplant are recruited into the graft where contribute to complement C3 deposition and neutrophil infiltration (engraftment syndrome) and fail to prolong graft survival (Casiraghi F, AJT 2012, 12:2373). Intragraft localization of MSC given post-transplant was also observed in syngeneic grafts, suggesting that ischemia/reperfusion injury could contribute to intragraft MSC recruitment. In search for mediators of this process and how to inhibit it with the final aim of MSC for deceased-donor kidney transplantation, we analyzed murine BM-MSC mRNA expression (by real time PCR) for C3a and C5a receptors (C3aR, C5aR) and found that these cells indeed express both C3aR and C5aR. To evaluate whether C3a and C5a (released during I/R induced-complement activation) play a role in intragraft recruitment of MSC, we administered BM-MSC labelled with PKH26 into syngeneic mice (500.000, iv) two days after allogeneic kidney transplant together with either C3aR (2 hours before MSC, ip; together with MSC, iv; 12 hours later, ip; 15 mg/kg/each) or C5aR (5 mg/kg/each) antagonists. MSC localization into the kidney and spleen was analyzed by fluorescence microscopy 24 hr after MSC infusion. MSC number into the graft was significantly reduced (PKH26+MSC/mm2; C3aRA: 11.8±1.6; C5aRA: 8.8±5.9) while increased into the spleen (PKH26+MSC/mm2; C3aRA: 293±72; C5aRA: 267±79) in mice given anaphylatoxin receptor antagonists compared to untreated transplanted mice given only MSC (PKH26+MSC/mm2; kidney 42.4±15.9; spleen 182±8, p<0.05). To evaluate whether the effect of C3aRA and C5aRA to favour MSC homing into the spleen would restore MSC tolerogenic properties in this setting we assessed kidney graft survival in mice given post-transplant MSC with or without C3aRA or C5aRA. MSC in the presence of C3aRA and C5aRA did not induce engraftment syndrome and showed a trend toward longer kidney survival (median survival time-days; MSC+C3aRA: 17; MSC+C5aRA: 14.5, MSC: 7.5; C3aRA: 8 days, C5aRA: 10 days). Further studies are however required to optimize efficacy of post-transplant MSC and C3aR and C5aR antagonists.
To cite this abstract in AMA style:Casiraghi F, Todeschini M, Azzollini N, Cravedi P, Heeger P, Cassis P, Solini S, Perico N, Noris M, Remuzzi G. Mesenchymal Stromal Cells (MSCs) Given Post-Transplant Together With C3a and C5a Receptor Antagonists Prevent Engraftment Syndrome and Induce a Mild Not-Significant Prolongation of Graft Survival [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/mesenchymal-stromal-cells-mscs-given-post-transplant-together-with-c3a-and-c5a-receptor-antagonists-prevent-engraftment-syndrome-and-induce-a-mild-not-significant-prolongation-of-graft-survival/. Accessed April 15, 2021.
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