Cornell University

The Alpha-Gal Syndrome and Hypersensitivity to Biomaterials: Understanding Xenoimmunity.

Biomaterials derived from nonhuman mammals are increasingly used in cardiovascular interventions, yet xenoimmune responses to these materials can complicate these procedures. Xenoimmunity describes the immune response mounted against foreign cells, tissues, or organs from different species. Alpha-gal syndrome, a tick-acquired IgE-mediated allergy to galactose-alpha-1,3-galactose, exemplifies this challenge. Patients face risk when exposed to porcine heparin, gelatin-based hemostatic agents, or bioprosthetic heart valves, with reactions ranging from delayed urticaria to immediate anaphylaxis. Alpha-gal sensitization has been linked to accelerated bioprosthetic valve degeneration and increased atherosclerotic plaque burden, suggesting that chronic immune activation may contribute to progressive cardiovascular disease. Cardiovascular hypersensitivity extends beyond alpha-gal syndrome. Drug-eluting stents with polymer coatings and metal alloys can trigger reactions that manifest as late thrombosis and restenosis. Cardiac implantable electronic devices cause hypersensitivity reactions in approximately 2% of recipients through titanium, nickel, and polymer components. Medications including protamine and iodinated contrast can precipitate life-threatening reactions through multiple immunologic pathways. Kounis syndrome and hypersensitivity myocarditis represent the most severe manifestations, where allergic responses directly cause acute coronary events or inflammatory cardiomyopathy. Recognition and prevention require coordinated clinical strategies. Systematic screening in tick-endemic regions helps identify at-risk patients before procedures. Multidisciplinary collaboration between cardiology and allergy specialists enables personalized prophylaxis tailored to sensitization profiles, while emerging diagnostic tools may distinguish benign antibody presence from clinically significant disease. Future progress depends on engineering cardiovascular devices that eliminate xenoantigenic epitopes and developing biomarkers that predict reaction risk. Clinicians must maintain awareness to recognize and prevent immune-mediated complications in susceptible patients.

Alpha-Gal Syndrome and Aortic Valve Replacement.

Alpha-gal syndrome (AGS) is an IgE-mediated hypersensitivity response to galactose-alpha-1,3-galactose (alpha-gal), an oligosaccharide present in beef and pork. This complicates bioprosthetic heart valve selection, as both bovine and porcine valves contain alpha-gal, posing risks of allergic reaction and potentially accelerated structural valve degeneration. A 78-year-old man with AGS and severe symptomatic aortic stenosis underwent transcatheter aortic valve replacement with a porcine-derived Evolut FX 29-mm valve following multidisciplinary evaluation. Preoperative allergist-guided prophylaxis, including IgE risk stratification, antihistamines, and corticosteroids, enabled successful implantation without complications. Bioprosthetic valves may pose unique risks for individuals sensitized to alpha-gal, where an alpha-gal IgE to total IgE ratio ≤5% is a proposed threshold in which patients can be rechallenged with animal products. This case highlights the successful management of a slightly higher ratio. The interplay between AGS, bioprosthetic valve selection, and structural valve durability necessitates an individualized approach to mitigate the hypersensitivity risks.

Alpha-gal-related bilateral orbital inflammatory syndrome in a strict vegan.

Topical α-gal nanoparticles accelerate diabetic wound healing.

An inadequate response from macrophages, key orchestrators of the wound healing process, has been implicated in the pathophysiology of impaired healing in diabetes. This study explored the utility of nanoparticles presenting the α-gal (Galα1-3Galβ1-4GlcNAc-R) epitope to induce anti-Gal antibody-mediated local transient recruitment of macrophages to accelerate wound closure and healing in a diabetic murine model. α1,3galactosyltrasferase knockout mice were stimulated to produce anti-Gal antibodies and subsequently diabetes was induced by streptozotocin-induced β-cell destruction. Six mm full-thickness skin wounds were made and α-gal nanoparticles (AGN) were topically applied on postwounding days 0 and 1. Wounds were analysed histologically for macrophage invasion and markers of wound healing, including epithelialization, vascularization and granulation tissue deposition through postoperative day 12. We found that application of AGN transiently but significantly increased macrophage recruitment into the wounds of diabetic mice. Treated wounds demonstrated more rapid closure and enhanced wound healing as demonstrated by significantly accelerated rates of epithelialization, vascularization and granulation tissue deposition. Thus, topical treatment of full-thickness wounds in diabetic mice with α-gal nanoparticles induced a transient but significant increase in macrophage recruitment resulting in an accelerated rate of wound healing. Using α-gal nanoparticles as a topical wound healing adjunct is a simple, safe and effective means of augmenting dysregulated macrophage recruitment present in the diabetic state.

Superselective intraarterial cerebral infusion of cetuximab after osmotic blood/brain barrier disruption for recurrent malignant glioma: phase I study.

Objective To establish a maximum tolerated dose of superselective intraarterial cerebral infusion (SIACI) of Cetuximab after osmotic disruption of the blood-brain barrier (BBB) with mannitol, and examine safety of the procedure in patients with recurrent malignant glioma. Methods A total of 15 patients with recurrent malignant glioma were included in the current study. The starting dose of Cetuximab was 100 mg/m(2) and dose escalation was done to 250 mg/m(2). All patients were observed for 28 days post-infusion for any side effects. Results There was no dose-limiting toxicity from a single dose of SIACI of Cetuximab up to 250 mg/m(2) after osmotic BBB disruption with mannitol. A tolerable rash was seen in 2 patients, anaphylaxis in 1 patient, isolated seizure in 1 patient, and seizure and cerebral edema in 1 patient. Discussion SIACI of mannitol followed by Cetuximab (up to 250 mg/m(2)) for recurrent malignant glioma is safe and well tolerated. A Phase I/II trial is currently underway to determine the efficacy of SIACI of cetuximab in patients with high-grade glioma.

Protein glycosylation in Parelaphostrongylus tenuis--first description of the Galalpha1-3Gal sequence in a nematode.

The white-tailed deer is the definitive host of the parasitic nematode Parelaphostrongylus tenuis. This parasite also infects a wide variety of domesticated livestock, causing a debilitating neurologic disease. Glycoconjugates are becoming increasingly implicated in nematode strategies to maintain persistent infections in immunologically competent hosts. In this study, we have carried out detailed mass spectrometric analysis together with classical biochemical techniques, including western blotting and immunohistochemical staining with anticarbohydrate monoclonal antibodies and have shown that P. tenuis contains complex-type N-glycans with the antennae capped with Galalpha1-3Galbeta1-4GlcNAc sequence. By mimicking a vertebrate glycan, Galalpha1-3Gal may aid the parasite in evading immunological detection by the host. This is the first report of the Galalpha1-3Gal sequence in a nematode.

Cutaneous reactions to chemotherapy and their management.

International data from 2002 report 10.9 million new cases of cancer and 6.7 million cancer deaths. Chemotherapy is an essential component in the multidisciplinary management of most cancers. Cutaneous reactions to chemotherapeutics are common and may contribute significantly to the morbidity, and rarely to the mortality, of patients undergoing such treatments. Recognition and management of these reactions is important to provide optimal care. This article aims to present the most common cutaneous reactions to frequently used chemotherapies and provides management guidelines. A MEDLINE search from 1966 through June 2005 was conducted to identify reports of common cutaneous toxicities with systemic chemotherapy and their appropriate management. An analysis of our literature search is presented in review form outlining common chemotherapy-related cutaneous reactions and their management, as well as the chemotherapeutics responsible for the cutaneous toxicity. Chemotherapy-related cutaneous toxicity includes generalized rashes such as the spectrum between erythema multiforme and toxic epidermal necrolysis, and site-specific toxicity such as mucositis, alopecia, nail changes, extravasation reactions, or hand-foot syndrome. Most of the toxicity is reversible with chemotherapy dose reductions or delays. Certain toxicities can be effectively treated or prevented, allowing optimal delivery of chemotherapy (e.g. premedications to prevent hypersensitivity, prophylactic mouthwashes to prevent mucositis). Newer non-chemotherapeutic targeted therapies such as epidermal growth factor receptor inhibitors (e.g. gefitinib, cetuximab) may also be associated with cutaneous toxicity and can be distressing for patients. Recent data suggest that skin toxicity associated with these agents may correlate with efficacy. Cutaneous toxicity occurs frequently with chemotherapy and non-chemotherapeutic biologic therapies. Early recognition and treatment of the toxicity facilitates good symptom control, prevents treatment-related morbidity, and allows continuation of anti-cancer therapy.

Chemoenzymatic synthesis of the Salmonella group E1 core trisaccharide using a recombinant beta-(1-->4)-mannosyltransferase.

The chemical synthesis of the bacterial O-antigen from Salmonella serogroup E1, 3-O-(4-O-beta-D-mannopyranosyl-alpha-L-rhamnopyranosyl)-alpha-D-galactos e, presents a particular challenge because it contains a beta-(1-->4) mannosidic linkage to L-rhamnose. We report a chemoenzymatic synthesis of this crucial antigenic material which culminates in the enzymatic formation of the critical beta-mannosyl connection catalyzed by Salmonella GDP-alpha-D-Man:alpha Rha1-->3 alpha Gal-PP-Und beta-(1-->4)-mannosyltransferase (ManT beta 4). In comparison with previous synthetic routes, this method is advantageous since it utilizes intermediates, available in significant yield, which can be readily derivatized from the reducing end to present flexibility for analog construction, while the enzymatic construction of the Man1-->4Rha glycosidic bond is both rapid and occurs in high yield. Furthermore, the reported spectroscopic and enzymatic structural characterization of the trisaccharide product furnishes the first indisputable functional link between wbaO and ManT beta 4 and clearly sets the stage for the future mechanistic study and exploitation of this fascinating glycocatalyst.