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α-Gal: Antibody Stimulated, Macrophage Directed Wound Healing
Omer Kaymakcalan, MD1, Xue Dong, BS1, Julia Jin, BS1, Rachel Akintayo, MD1, Kerry Morrison, BA1, Ross Weinreb, BS1, Yoshi Toyoda, BA1, Uri Galili, PhD2, Jason Spector, MD1.
1Weill Cornell Medical College, New York, NY, USA, 2University of Massachusetts Medical Center, Worcester, MA, USA.

BACKGROUND: Macrophages are the crucial mediator of the wound healing response. Attracted by foreign bodies and inflammatory chemokines, they modulate the immune response and coordinate the transition to healing by the release of a variety of cytokines and growth factors. The most potent activators of macrophages, in fact, are the Fc region of antibodies as well as compliment released by activated antigen-antibody complexes. In turn, the most prevalent group of antibodies in the human immune system, 1% of the total, is directed against the glycoprotein and glycolipid antigens: Galα1-3Galβ1-4GlcNAc-R (α-gal). These α-gal antigens are naturally occurring, with the human body encountering it safely and continuously in the enteric tract. Given that in humans α-gal antigens have consistently high levels of corresponding antibodies (anti-gal) directed against them, this is a prime target for investigation as a natural means to stimulate macrophages and thereby facilitate wound healing.
Wild type mice naturally generate α-gal and thus do not express anti-gal, therefore we used α-1,3 galactosyltrasferase knockout mice (α-1,3GT KO mice). The mice were stimulated to produce the α-1,3GT anti-gal at titers comparable to humans. Following an established murine wound model, bilateral 6 mm dorsal full-thickness splinted skin wounds were created and the mice were then treated with a one-time dose of α-gal nanoparticles or sterile saline directly into the wound. On post-op days 1, 2, 3, 6, and 9 mice from each group were euthanized and the wounds were harvested for analysis.
By post-op day 3, mice treated with α-gal containing nanoparticles demonstrated an increased rate of keratinization, with average keratinocyte migration of 225.7 μm versus 143.1 μm, (p value 0.23, ns). By 6 days post-op, mice treated with α-gal containing nanoparticles demonstrated a significantly increased rate of keratinization, with average keratinocyte migration of 2376 μm versus 986.4 μm, p < .0002, with 6/8 experimental wounds completely healed versus only 1/8 control wounds. Furthermore, immunofluorescence staining for CD11b demonstrated increased macrophage invasion into the wounds of α-gal nanoparticle treated wounds and at earlier time-points compared to saline control.
A one-time application α-gal nanoparticles stimulated early and increased macrophage invasion into wounds, and a subsequently enhanced wound healing response. This approach may be translated to human application, as a simple and natural means to enhance wound healing in both normal and pathologic conditions.

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