Cell surface ␣(1,3)-and ␣(1,4)-fucosylated oligosaccharides have received a substantial amount of attention because some are thought to be essential to the initiation of immune cell adhesion to vascular endothelium during the inflammatory process (reviewed in Refs. 1-5 and 6 -15). This is perhaps best characterized by the "rolling" type of adhesion mediated by interactions between sialyl Lewis x (sLe x )-bearing glycoconjugates on leukocytes and P-and E-selectin expressed by activated vascular endothelium (5). Animal intervention studies indicate that such fucosylated oligosaccharide molecules can act as anti-inflammatory agents by inhibiting leukocyte-endothelial cell interactions (15-18). Furthermore, absence of such molecules on the leukocytes of individuals with the rare human leukocyte adhesion II syndrome is associated with profound defects in leukocyte-endothelial cell adhesion and with nonpyogenic infections (19,20). These observations suggest that compounds capable of specifically inhibiting leukocyte sialyl Lewis x expression might represent candidates for anti-inflammatory pharmacologic agents.The ␣(1,3)-fucosyltransferases (␣(1,3)-Fuc-Ts) 1 represent a target for such inhibitory agents, since synthesis and expression of the sLe x molecule and related ␣(1,3)-and ␣(1,4)-fucosylated oligosaccharides are controlled, in large measure, by ␣(1,3)Fuc-Ts (5). These enzymes catalyze the attachment of L-fucose in ␣ anomeric linkage to one or more distinct oligosaccharide precursors. Biochemical and molecular cloning studies indicate that the human genome encodes at least five distinct ␣(1,3)-Fuc-Ts (9, 21-28; reviewed in Refs. 5, 29, and 30). Each enzyme can react with one or more structurally distinct oligosaccharides and can thereby generate a unique spectra of cell surface ␣(1,3)-fucosylated oligosaccharide products. In turn, these molecules may exhibit distinct biologic functions, including those involving selectin-dependent cell adhesion.Although the primary sequences are known for several ␣(1,3)-Fuc-Ts (9, 21-28), the structural determinants within these enzymes that dictate their different substrate specificities remain undefined. The purpose of this work is to identify such protein sequence(s) and to provide a conceptual background for work to design or identify molecules that might inhibit ␣(1,3)-Fuc-Ts by interacting with acceptor substrate binding sites.In this study, we chose to explore three human ␣(1,3)-Fuc-Ts (Fuc-TIII, Fuc-TV, and Fuc-TVI) with informative structural and catalytic properties. These enzymes share approximately 85% overall amino acid sequence identity (24,25). The COOH termini of these enzymes maintain nearly identical amino acid sequences, whereas their NH 2 -terminal regions are punctuated by foci of nonidentical amino acids; we term these regions "hypervariable" segments. These three enzymes maintain shared and distinct acceptor substrate specificities. In partic-
2421 Poster Board II-398 Atypical hemolytic uremic syndrome (aHUS) is a rare thrombotic microangiopathy characterized by microangiopathic hemolytic anemia, consumptive thrombocytopenia, and acute renal failure (ARF). The prognosis for aHUS is poor as 25% of patients die during acute phases of the disease and 50% progress to end stage renal disease (ESRD). A high percentage of patients with aHUS experience recurrence and graft failure following renal transplantation. This report summarizes the successful use of a terminal complement inhibitor as a treatment for aHUS following renal transplant with demonstration of both clinical and pathological resolution of aHUS in a patient who was resistant to plasma therapy. A 34-year-old female with ESRD due to aHUS underwent living related renal transplantation. Approximately one month after renal transplantation, she presented with acute renal failure (ARF), with creatinine (Cr) increasing from 1.2 to 2.2 mg/dl. The renal biopsy showed thrombotic microangiopathy (TMA). ADAMTS-13 activity was normal. Tacrolimus was discontinued and corticosteroids were initiated. She responded to 14 sessions of every-other-day plasma exchange (PLEX), with stabilization of her creatinine at 1.5mg/dl. At month 5, she again presented with ARF with a renal biopsy showing TMA. PLEX was initiated once again (3 times per week) but her serum creatinine did not improve significantly during PLEX from month 5 to month 9 and ranged from 1.9 to 2.3 mg/dL with urine protein:creatinine ratio of 1.7 to 3.0. Elevations of Cr (2.34 to 3.65mg/dLl), modest elevations in LDH (209 to 380 IU/L) and ∼20% decrease in platelets (227 to 185 × 109/L) were observed when PLEX was interrupted. Diagnostic renal biopsy during this period of PLEX dependency displayed ongoing TMA. With ongoing persistent TMA despite maximal PLEX, at month 9, treatment with eculizumab, a humanized monoclonal antibody that blocks the cleavage of the terminal complement molecule C5 and generation of pro-inflammatory C5a and C5b-9, was initiated. The patient was dosed with eculizumab 900mg weekly for 4 weeks followed by 1200mg at week 5 and 1200mg every 2 weeks thereafter. After 4 weeks of induction therapy with eculizumab and no PLEX sessions, her serum creatinine stabilized at 4.0 to 4.3 mg/dL. At month 10 post transplant, and 7 weeks after the switch from PLEX to eculizumab, renal biopsy now showed no TMA and moderate residual interstitial fibrosis. Fifteen (15) months post transplant and 6 months of eculizumab treatment, the patient continues on eculizumab maintenance therapy with no requirement for PLEX. She is experiencing her best stable renal function to date, with Cr=2.7 mg/dL, a urine protein:creatinine ratio of 2.29 as well as normal platelet counts and slightly elevated LDH (∼350 IU/L) with normal haptoglobin. These results demonstrate that PLEX following recurrent aHUS post transplant did not stabilize renal function and biopsy-proven TMA persisted despite intensive PLEX therapy post transplant. In contrast, switch of PLEX to chronic terminal complement inhibitor treatment with eculizumab resolved the TMA process, stabilized and improved the transplanted kidney function, and eliminated the need for PLEX for this patient with recurrent aHUS post transplant. Clinical trials to further investigate and confirm the efficacy of eculizumab in the treatment of aHUS are ongoing. Disclosures: Legault: Alexion Pharmaceuticals: Research Funding. Off Label Use: Eculizumab, a terminal complement inhibitor, used to treat aHUS.
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