David Gies
Alexion Pharmaceuticals
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Publication
Featured researches published by David Gies.
Journal of Immunology | 2007
Hao Wang; Jacqueline Arp; Weihua Liu; Susan Faas; Jifu Jiang; David Gies; Siobhan Ramcharran; Bertha Garcia; Robert Zhong; Russell P. Rother
Ab-mediated rejection (AMR) remains the primary obstacle in presensitized patients following organ transplantation, as it is refractory to anti-T cell therapy and can lead to early graft loss. Complement plays an important role in the process of AMR. In the present study, a murine model was designed to mimic AMR in presensitized patients. This model was used to evaluate the effect of blocking the fifth complement component (C5) with an anti-C5 mAb on prevention of graft rejection. BALB/c recipients were presensitized with C3H donor skin grafts 7 days before heart transplantation from the same donor strain. Heart grafts, transplanted when circulating anti-donor IgG Abs were at peak levels, were rejected in 3 days. Graft rejection was characterized by microvascular thrombosis and extensive deposition of Ab and complement in the grafts, consistent with AMR. Anti-C5 administration completely blocked terminal complement activity and local C5 deposition, and in combination with cyclosporine and short-term cyclophosphamide treatment, it effectively prevented heart graft rejection. These recipients achieved permanent graft survival for >100 days with normal histology despite the presence of systemic and intragraft anti-donor Abs and complement, suggesting ongoing accommodation. Furthermore, double-transplant experiments demonstrated that immunological alterations in both the graft and the recipient were required for successful graft accommodation to occur. These data suggest that terminal complement blockade with a functionally blocking Ab represents a promising therapeutic approach to prevent AMR in presensitized recipients.
American Journal of Transplantation | 2008
Russell P. Rother; J. Arp; J. Jiang; Wei Ge; Susan Faas; Weihua Liu; David Gies; Anthony M. Jevnikar; Bertha Garcia; H. Wang
We explored whether a functionally blocking anti‐C5 monoclonal antibody (mAb) combined with T‐ and B‐cell immunosuppression can successfully prevent antibody‐mediated (AMR) and cell‐mediated rejection (CMR) in presensitized murine recipients of life‐supporting kidney allografts. To mimic the urgent clinical features of AMR experienced by presensitized patients, we designed a murine model in which BALB/c recipients were presensitized with fully MHC‐mismatched C3H donor skin grafts one week prior to C3H kidney transplantation. Presensitized recipients demonstrated high levels of circulating and intragraft antidonor antibodies and terminal complement activity, rejecting grafts within 8.5 ± 1.3 days. Graft rejection was predominantly by AMR, characterized by interstitial hemorrhage, edema and glomerular/tubular necrosis, but also demonstrated moderate cellular infiltration, suggesting CMR involvement. Subtherapeutic treatment with cyclosporine (CsA) and LF15–0195 (LF) did not significantly delay rejection. Significantly, however, the addition of anti‐C5 mAb to this CsA/LF regimen prevented terminal complement activity and inhibited both AMR and CMR, enabling indefinite (>100 days) kidney graft survival despite the persistence of antidonor antibodies. Long‐term surviving kidney grafts expressed the protective proteins Bcl‐xS/L and A‐20 and demonstrated normal histology, suggestive of graft accommodation or tolerance. Thus, C5 blockade combined with routine immunosuppression offers a promising approach to prevent graft loss in presensitized patients.
Journal of Immunology | 2001
Michael C. Montalto; Charles D. Collard; Jon A. Buras; Wende R. Reenstra; Rebecca McClaine; David Gies; Russell P. Rother; Gregory L. Stahl
Complement plays a significant role in mediating endothelial injury following oxidative stress. We have previously demonstrated that the lectin complement pathway (LCP), which is initiated by deposition of the mannose-binding lectin (MBL), is largely responsible for activating complement on endothelial cells following periods of oxidative stress. Identifying functional inhibitors that block MBL binding will be useful in characterizing the role of the LCP in disease models. The human cytokeratin peptide SFGSGFGGGY has been identified as a molecular mimic of N-acetyl-d-glucosamine (GlcNAc), a known ligand of MBL. Thus, we hypothesized that this peptide would specifically bind to MBL and functionally inhibit the LCP on endothelial cells following oxidative stress. Using a BIAcore 3000 optical biosensor, competition experiments were performed to demonstrate that the peptide SFGSGFGGGY inhibits binding of purified recombinant human MBL to GlcNAc in a concentration-dependent manner. Solution affinity data generated by BIAcore indicate this peptide binds to MBL with an affinity (KD) of 5 × 10−5 mol/L. Pretreatment of human serum (30%) with the GlcNAc-mimicking peptide (10–50 μg/ml) significantly attenuated MBL and C3 deposition on human endothelial cells subjected to oxidative stress in a dose-dependent manner, as demonstrated by cell surface ELISA and confocal microscopy. Additionally, this decapeptide sequence attenuated complement-dependent VCAM-1 expression following oxidative stress. These data indicate that a short peptide sequence that mimics GlcNAc can specifically bind to MBL and functionally inhibit the proinflammatory action of the LCP on oxidatively stressed endothelial cells.
Transplantation | 2005
Hao Wang; Jifu Jiang; Weihua Liu; Dalibor Kubelik; Gang Chen; David Gies; Bertha Garcia; Robert Zhong; Russell P. Rother
Archive | 2011
David Gies; Jeffrey W. Hunter; Jeremy P. Springhorn
Archive | 2006
Anke Kretz-Rommel; Naveen Dakappagari; Martha A. Wild; Cecilia Orencia; Katherine S. Bowdish; David Gies; Jeremy P. Springhorn
Archive | 2010
Jeremy P. Springhorn; David Gies
Archive | 2017
David Gies; Jeremy P. Springhorn
Archive | 2010
Jeremy P. Springhorn; David Gies
Archive | 2010
Jeremy P. Springhorn; David Gies