α-Gal Nanoparticles in Wound and Burn Healing Acceleration
Abstract
Significance: Rapid recruitment and activation of macrophages may accelerate wound healing. Such accelerated healing was observed in wounds and burns of experimental animals treated with α-gal nanoparticles.
Recent Advances: α-Gal nanoparticles present multiple α-gal epitopes (Galα1-3Galβ1-4GlcNAc-R). α-Gal nanoparticles applied to wounds bind anti-Gal (the most abundant antibody in humans) and generate chemotactic complement peptides, which rapidly recruit macrophages. Fc/Fc receptor interaction between anti-Gal coating the α-gal nanoparticles and recruited macrophages activates macrophages to produce cytokines that accelerate healing. α-Gal nanoparticles applied to burns and wounds in mice and pigs producing anti-Gal, decreased healing time by 40–60%. In mice, this accelerated healing avoided scar formation. α-Gal nanoparticle-treated wounds, in diabetic mice producing anti-Gal, healed within 12 days, whereas saline-treated wounds became chronic wounds. α-Gal nanoparticles are stable for years and may be applied dried, in suspension, aerosol, ointments, or within biodegradable materials.
Critical Issues: α-Gal nanoparticle therapy can be evaluated only in mammalian models producing anti-Gal, including α1,3-galactosyltransferase knockout mice and pigs or Old World primates. Traditional experimental animal models synthesize α-gal epitopes and lack anti-Gal.
Future Directions: Since anti-Gal is naturally produced in all humans, it is of interest to determine safety and efficacy of α-gal nanoparticles in accelerating wound and burn healing in healthy individuals and in patients with impaired wound healing such as diabetic patients and elderly individuals. In addition, efficacy of α-gal nanoparticle therapy should be studied in healing and regeneration of internal injuries such as surgical incisions, ischemic myocardium following myocardial infarction, and injured nerves.
Get full access to this article
View all available purchase options and get full access to this article.
About the Author
Uri Galili, PhD, received his PhD degree in Immunology in 1977 at the Hebrew University School of Medicine, Jerusalem, Israel. He did his postdoctoral research in the Department of Tumor Biology at the Karolinska Institute, Stockholm, Sweden (1977). Subsequently, he performed his research at Hadassah Medical Center, Jerusalem, Israel (1979–1984), where he discovered the natural anti-Gal antibody as the most abundant natural antibody in humans. He continued in 1984 his research in the United States as professor at the University of California Medical Center, San Francisco, CA, where he identified the α-gal epitope as the antigen recognized by anti-Gal and studied the molecular basis for the evolution of the natural anti-Gal antibody and the α-gal epitope in mammals. At MCP Hahnemann School of Medicine, Philadelphia, PA (1991), he studied the significance of anti-Gal/α-gal epitope interaction in mediating hyperacute rejection of pig xenografts and initiated studies on harnessing the immunologic potential of anti-Gal in cancer immunotherapy and in amplification of immune response to microbial vaccines. Subsequently, at Rush Medical School, Chicago, IL (1999), he developed methods for preventing anti-Gal production by inducing immune tolerance to the α-gal epitope. After moving to UMass Medical School, Worcester, MA (2004), he developed a method for in situ conversion of tumors into autologous vaccines targeted to antigen-presenting cells by intratumoral injection of α-gal glycolipids and performed clinical trials with this novel immunotherapy. At UMass Medical School, he further developed the α-gal nanoparticles, which enable harnessing of anti-Gal for induction of accelerated wound and burn healing and for induction of tissue repair and regeneration in internal injuries. Dr. Galili retired in 2013 and presently volunteers as scientific researcher at Rush Medical School, Chicago, IL.
References
1.
DiPietro LA, Koh TJ. Macrophages and wound healing. Adv Wound Care 2016;2:71–75.
2.
Singer AJ, Clark RA. Cutaneous wound healing. N Engl J Med 1999;341:738–746.
3.
Martin P. Wound healing—aiming for perfect skin regeneration. Science 1997;276:75–81.
4.
Piccolo MT, Wang Y, Sannomiya P, et al. Chemotactic mediator requirements in lung injury following skin burns in rats. Exp Mol Pathol 1999;66:220–226.
5.
Low QE, Drugea IA, Duffner LA, et al. Wound healing in MIP-1α(-/-) and MCP-1(-/-) mice. Am J Pathol 2001;159:457–463.
6.
Heinrich SA, Messingham KA, Gregory MS, et al. Elevated monocyte chemoattractant protein-1 levels following thermal injury precede monocyte recruitment to the wound site and are controlled, in part, by tumor necrosis factor-α. Wound Repair Regen 2003;11:110–119.
7.
Snyderman R, Pike M. 1984. Chemoattractant receptors on phagocytic cells. Annu Rev Immunol 2003;2:257–281.
8.
Galili U, Rachmilewitz EA, Peleg A, Flechner I. A unique natural human IgG antibody with anti-α-galactosyl specificity. J Exp Med 1984;160:1519–1531.
9.
Galili U. Anti-Gal: an abundant human natural antibody of multiple pathogeneses and clinical benefits. Immunology 2013;140:1–11.
10.
Yu PB, Holzknecht ZE, Bruno D, Parker W, Platt JL. Modulation of natural IgM binding and complement activation by natural IgG antibodies. J Immunol 1996;157:5163–5168.
11.
Parker W, Lin SS, Yu PB, et al. Naturally occurring anti-α-galactosyl antibodies: relationship to xenoreactive anti-α-galactosyl antibodies. Glycobiology 1999;9:865–873.
12.
Teranishi K, Manez R, Awwad M, Cooper DK. Anti-Gal α1-3Gal IgM and IgG antibody levels in sera of humans and old world non-human primates. Xenotransplantation 2002;9:148–154.
13.
Wang L, Anaraki F, Henion TR, Galili U. Variations in activity of the human natural anti-Gal antibody in young and elderly populations. J Gerontol (Med Sci). 1995;50A:M227–M233.
14.
Galili U, Mandrell RE, Hamadeh RM, Shohet SB, Griffis JM. Interaction between human natural anti-α-galactosyl immunoglobulin G and bacteria of the human flora. Infect Immun 1988;56:1730–1737.
15.
Posekany KJ, Pittman HK, Bradfield JF, Haisch CE, Verbanac KM. Induction of cytolytic anti-Gal antibodies in α-1,3-galactosyltransferase gene knockout mice by oral inoculation with Escherichia coli O86:B7 bacteria. Infect Immun 2002;70:6215–6222.
16.
Galili U, Macher BA, Buehler J, Shohet SB. Human natural anti-α-galactosyl IgG. II. The specific recognition of α(1–3)-linked galactose residues. J Exp Med 1985;162:573–582.
17.
Macher BA, Galili U. The Galα1,3Galβ1,4GlcNAc-R (α-Gal) epitope: a carbohydrate of unique evolution and clinical relevance. Biochem Biophys Acta 2008;1780:75–88.
18.
Galili U, Clark MR, Shohet SB, Buehler J, Macher BA. Evolutionary relationship between the anti-Gal antibody and the Galα1 → 3Gal epitope in primates. Proc Natl Acad Sci USA 1987;84:1369–1373.
19.
Galili U, Shohet SB, Kobrin E, Stults CLM, Macher BA. Man, apes, and Old World monkeys differ from other mammals in the expression of α-galactosyl epitopes on nucleated cells. J Biol Chem 1988;263:17755–17762.
20.
Oriol R, Candelier JJ, Taniguchi S, et al. Major carbohydrate epitopes in tissues of domestic and African wild animals of potential interest for xenotransplantation research. Xenotransplantation 1999;6:79–89.
21.
Good AH, Cooper DK, Malcolm AJ, et al. Identification of carbohydrate structures which bind human anti-porcine antibodies: implication for discordant xenografting in man. Transplant Proc 1992;24:559–562.
22.
Galili U. Interaction of the natural anti-Gal antibody with α-galactosyl epitopes: a major obstacle for xenotranplantation in humans. Immunol Today 1993;14:480–482.
23.
Sandrin MS, McKenzie IF. Galα(1,3)Gal, the major xenoantigen(s) recognised in pigs by human natural antibodies. Immunol Rev 1994;141:169–190.
24.
Collins BH, Cotterell AH, McCurry KR, et al. Cardiac xenografts between primate species provide evidence of the α-galactosyl determinant in hyperacute rejection. J Immunol 1994;154:5500–5510.
25.
Simon PM, Neethling FA, Taniguchi S, et al. Intravenous infusion of Galα1-3Gal oligosaccharides in baboon delays hyperacute rejection of porcine heart xenografts. Transplantation 1998;56:346–353
26.
Xu Y, Lorf T, Sablinski T, et al. Removal of anti-porcine natural antibodies from human and nonhuman primate plasma in vitro and in vivo by a Galα1-3Galβ14Glc-R immunoaffinity column. Transplantation 1998;65:172–179.
27.
Galili U, Wigglesworth K, Abdel-Motal UM. Accelerated healing of skin burns by anti-Gal/α-gal liposomes interaction. Burns 2010;36:239–251.
28.
Wigglesworth K, Racki WJ, Mishra R, Szomolanyi-Tsuda E, Greiner DL, Galili U. Rapid recruitment and activation of macrophages by anti-Gal/α-gal liposome interaction accelerates wound healing. J Immunol 2011;186:4422–4432.
29.
Hurwitz Z, Ignotz R, Lalikos J, Galili U. Accelerated porcine wound healing with α-Gal nanoparticles. Plast Reconst Surg 2012;129:242–251.
30.
Eto T, Iichikawa Y, Nishimura K, Ando S, Yamakawa T. Chemistry of lipids of the posthemolytic residue or stroma of erythrocytes. XVI. Occurance of ceramide pentasaccharide in the membrane of erythrocytes and reticulocytes in rabbit. J Biochem (Tokyo) 1968;64:205–213.
31.
Stellner K, Saito H, Hakomori S. Determination of aminosugar linkage in glycolipids by methylation. Aminosugar linkage of ceramide pentasaccharides of rabbit erythrocytes and of Forssman antigen. Arch Biochem Biophys 1973;133:464–472.
32.
Dabrowski U, Hanfland P, Egge H, Kuhn S, Dabrowski J. Immunochemistry of I/i-active oligo- and polyglycosylceramides from rabbit erythrocyte membranes. Determination of branching patterns of a ceramide pentadecasaccharide by 1H nuclear magnetic resonance. J Biol Chem 1984;259:7648–7651.
33.
Egge H, Kordowicz M, Peter-Katalinic J, Hanfland P. Immunochemistry of I/i-active oligo- and polyglycosylceramides from rabbit erythrocyte membranes. J Biol Chem 1985;260:4927–4935.
34.
Hanfland P, Kordowicz M, Peter-Katalinić J, Egge H, Dabrowski J, Dabrowski U. Structure elucidation of blood group B-like and I-active ceramide eicosa- and pentacosasaccharides from rabbit erythrocyte membranes by combined gas chromatography-mass spectrometry; electron-impact and fast-atom-bombardment mass spectrometry; and two-dimensional correlated, relayed-coherence transfer, and nuclear Overhauser effect 500-MHz 1H-n.m.r. spectroscopy. Carbohydr Res 1988;178:1–21.
35.
Ogawa H., and Galili U. Profiling terminal N-acetyllactoamines of glycans on mammalian cells by an immuno-enzymatic assay. Glycoconjugate J 2006;23:663–674.
36.
Galili U, Wigglesworth K, Abdel-Motal UM. Intratumoral injection of α-gal glycolipids induces xenograft-like destruction and conversion of lesions into endogenous vaccines. J Immunol 2007;178:4676–4687.
37.
Thall AD, Maly P, Lowe JB. Oocyte Gal α1,3Gal epitopes implicated in sperm adhesion to the zona pellucida glycoprotein ZP3 are not required for fertilization in the mouse. J Biol Chem 1995;270:21437–21440.
38.
Tearle RG, Tange MJ, Zannettino ZL, et al. The α-1,3-galactosyltransferase knockout mouse. Implications for xenotransplantation. Transplantation 1996;61:13–19.
39.
Lai L, Kolber-Simonds D, Park KW. et al. Production of α-1,3-galactosyltransferase knockout pigs by nuclear transfer cloning. Science 2002;295:1089–1092.
40.
Phelps CJ, Koike C, Vaught TD, et al. Production of α1,3-galactosyltransferase-deficient pigs. Science 2003;299:411–414.
41.
Dor FJ, Tseng YL, Cheng J, et al. α1,3-Galactosyltransferase gene-knockout miniature swine produce natural cytotoxic anti-Gal antibodies. Transplantation 2004;78:15–20.
42.
Fang J, Walters A, Hara H, et al. Anti-gal antibodies in α1,3-galactosyltransferase gene-knockout pigs. Xenotransplantation 2012;19:305–310.
43.
Galili U. α1,3Galactosyltransferase knockout pigs produce the natural anti-Gal antibody and simulate the evolutionary appearance of this antibody in primates. Xenotransplantation 2013;20:267–276.
44.
LaTemple DC, Galili U. Adult and neonatal anti-Gal response in knock-out mice for α-galactosyltransferase. Xenotransplantation 1998;5:191–196.
45.
Tanemura M, Yin D, Chong AS, Galili U. Differential immune response to α-gal epitopes on xenografts and allografts: implications for accommodation in xenotransplantation. J Clin Invest 2000;105:301–310.
46.
Commins SP, Satinover SM, Hosen J, et al. Delayed anaphylaxis, angioedema, or urticaria after consumption of red meat in patients with IgE antibodies specific for galactose-α-1,3-galactose. J Allergy Clin Immunol 2009;123:426–433.
47.
Morisset M, Richard C, Astier C, et al. Anaphylaxis to pork kidney is related to IgE antibodies specific for galactose-α-1,3-galactose. Allergy 2012;67:699–704.
48.
Nunez R, Carballada F, Gonzalez-Quintela A, Gomez-Rial J, Boquete M, Vidal C. Delayed mammalian meat-induced anaphylaxis due to galactose-α-1,3-galactose in 5 European patients. J Allergy Clin Immunol 2011;128:1122–1124.
49.
Falanga V. Wound healing and its impairment in the diabetic foot. Lancet 2005;366:1736–1743.
50.
Ochoa O, Torres FM, Shireman PK. Chemokines and diabetic wound healing. Vascular 2007;15:350–355.
Information & Authors
Information
Published In
Advances in Wound Care
Volume 6 • Issue Number 3 • March 2017
Pages: 81 - 92
Copyright
Copyright 2017, Mary Ann Liebert, Inc.
History
Published in print: March 2017
Published online: 1 March 2017
Published ahead of print: 8 November 2016
Accepted: 2 October 2016
Received: 29 August 2016
Topics
Authors
Author Disclosure and Ghostwriting
The author has no conflict of interests in the studies described in this review. The article was written by the author with no ghostwriting.
Metrics & Citations
Metrics
Citations
Export Citation
Export citation
Select the format you want to export the citations of this publication.
View Options
Access content
To read the fulltext, please use one of the options below to sign in or purchase access.⚠ Society Access
If you are a member of a society that has access to this content please log in via your society website and then return to this publication.