Research article Topical Sections

Incidence in plasma of low level antibodies against three xenotransplantation and immunotherapeutic glycan antigens

  • Received: 30 July 2020 Accepted: 17 September 2020 Published: 21 September 2020
  • Antibodies against xeno-glycan antigens terminating with the saccharides Galα, GalNAcα and Rhaα are ubiquitous in human blood. Although originating as barriers to infection some of these naturally occurring complement-activating antibodies also contribute to disease processes, hinder xenotransplantation and have potential medical roles in immuno-oncotherapy. Because concentration of antibody is important in determining biological activity, there is a need to understand population variation in naturally occurring antibody levels, and to be able to rapidly and accurately determine levels in individuals. Xeno-glycan antigens in the form of function-spacer-lipid constructs were used to modify human red cells (kodecytes) to have on their surface micromolar equivalents of the xeno-glycan antigens Galα1-3Galβ1-4GlcNAc, GalNAcα1-3Galβ1-4GlcNAc and Rhaα. The methodology used was based on a previously validated kodecyte method used for quantifying IgM and IgG ABO human blood group antibodies in undiluted plasma. We tested plasma samples from 100 healthy individuals against these three different xeno-glycan kodecytes with each at three different loading concentrations of antigen to determine relative levels of these antibodies in human plasma. Sixty-one samples were also independently tested by enzyme immunoassay to correlate levels of anti-Galα. Results demonstrate independence between antibody specificities and substantial variation between individuals in levels of these antibodies, with >92% of the population having medium or high levels of at least one specificity. However, of particular importance was that 5–8% of the population had low levels of both IgM and IgG to at least one specificity and these individuals would probably have a poor immediate response when challenged by the corresponding antigen.

    Citation: Holly E Perry, Ivan Ryzhov, Oxana Galanina, Nicolai V Bovin, Stephen M Henry. Incidence in plasma of low level antibodies against three xenotransplantation and immunotherapeutic glycan antigens[J]. AIMS Allergy and Immunology, 2020, 4(4): 75-87. doi: 10.3934/Allergy.2020007

    Related Papers:

  • Antibodies against xeno-glycan antigens terminating with the saccharides Galα, GalNAcα and Rhaα are ubiquitous in human blood. Although originating as barriers to infection some of these naturally occurring complement-activating antibodies also contribute to disease processes, hinder xenotransplantation and have potential medical roles in immuno-oncotherapy. Because concentration of antibody is important in determining biological activity, there is a need to understand population variation in naturally occurring antibody levels, and to be able to rapidly and accurately determine levels in individuals. Xeno-glycan antigens in the form of function-spacer-lipid constructs were used to modify human red cells (kodecytes) to have on their surface micromolar equivalents of the xeno-glycan antigens Galα1-3Galβ1-4GlcNAc, GalNAcα1-3Galβ1-4GlcNAc and Rhaα. The methodology used was based on a previously validated kodecyte method used for quantifying IgM and IgG ABO human blood group antibodies in undiluted plasma. We tested plasma samples from 100 healthy individuals against these three different xeno-glycan kodecytes with each at three different loading concentrations of antigen to determine relative levels of these antibodies in human plasma. Sixty-one samples were also independently tested by enzyme immunoassay to correlate levels of anti-Galα. Results demonstrate independence between antibody specificities and substantial variation between individuals in levels of these antibodies, with >92% of the population having medium or high levels of at least one specificity. However, of particular importance was that 5–8% of the population had low levels of both IgM and IgG to at least one specificity and these individuals would probably have a poor immediate response when challenged by the corresponding antigen.


    加载中


    Conflict of interests



    All authors declare no conflicts of interest in this paper.

    [1] von Gunten S, Smith DF, Cummings RD, et al. (2009) Intravenous immunoglobulin contains a broad repertoire of anticarbohydrate antibodies that is not restricted to the IgG2 subclass. J Allergy Clin Immunol 123: 1268-1276. doi: 10.1016/j.jaci.2009.03.013
    [2] Baumgarth N, Tung JW, Herzenberg LA (2005) Inherent specificities in natural antibodies: a key to immune defense against pathogen invasion. Springer Semin Immunopathol 26: 347-362. doi: 10.1007/s00281-004-0182-2
    [3] Bovin NV (2013) Natural antibodies to glycans. Biochemistry Moscow 78: 786-797. doi: 10.1134/S0006297913070109
    [4] Huflejt ME, Vuskovic M, Vasiliu D, et al. (2009) Anti-carbohydrate antibodies of normal sera: findings, surprises and challenges. Mol Immunol 46: 3037-3049. doi: 10.1016/j.molimm.2009.06.010
    [5] Khasbiullina NR, Bovin NV (2015) Hypotheses of the origin of natural antibodies: a glycobiologist's opinion. Biochemistry Moscow 80: 820-835. doi: 10.1134/S0006297915070032
    [6] Springer GF, Horton RE (1969) Blood group isoantibody stimulation in man by feeding blood group-active bacteria. J Clin Invest 48: 1280-1291. doi: 10.1172/JCI106094
    [7] Commins SP, Platts-Mills TA (2010) Allergenicity of carbohydrates and their role in anaphylactic events. Curr Allergy Asthma Rep 10: 29-33. doi: 10.1007/s11882-009-0079-1
    [8] Dunne DW (1990) Schistosome carbohydrates. Parasitol Today 6: 45-48. doi: 10.1016/0169-4758(90)90068-F
    [9] März L, Altmann F, Staudacher E, et al. (1995) Protein glycosylation in insects. New Comprehensive Biochemistry Amsterdam: Elsevier, 521.
    [10] Klein HG, Anstee DJ (2014)  Mollison's Blood Transfusion in Clinical Medicine Oxford: Wiley-Blackwell, 118.
    [11] Galili U, Rachmilewitz EA, Peleg A, et al. (1984) A unique natural human IgG antibody with anti-alpha-galactosyl specificity. J Exp Med 160: 1519-1531. doi: 10.1084/jem.160.5.1519
    [12] Wigglesworth KM, Racki WJ, Mishra R, et al. (2011) Rapid recruitment and activation of macrophages by anti-Gal/α-Gal liposome interaction accelerates wound healing. J Immunol 186: 4422-4432. doi: 10.4049/jimmunol.1002324
    [13] Galili U, Wigglesworth K, Abdel-Motal UM (2010) Accelerated healing of skin burns by anti-Gal/α-gal liposomes interaction. Burns 36: 239-251. doi: 10.1016/j.burns.2009.04.002
    [14] Hossain MK, Vartak A, Karmakar P, et al. (2018) Augmenting vaccine immunogenicity through the use of natural human anti-rhamnose antibodies. ACS Chem Biol 13: 2130-2142. doi: 10.1021/acschembio.8b00312
    [15] Galili U (2018)  The Natural Anti-Gal Antibody as Foe Turned Friend in Medicine London: Academic Press, 176.
    [16] Blixt O, Head S, Mondala T, et al. (2004) Printed covalent glycan array for ligand profiling of diverse glycan binding proteins. P Natl Acad Sci USA 101: 17033-17038. doi: 10.1073/pnas.0407902101
    [17] Vuskovic MI, Xu H, Bovin NV, et al. (2011) Processing and analysis of serum antibody binding signals from Printed Glycan Arrays for diagnostic and prognostic applications. Int J Bioinf Res Appl 7: 402-426. doi: 10.1504/IJBRA.2011.043771
    [18] Sheridan RTC, Hudon J, Hank JA, et al. (2014) Rhamnose glycoconjugates for the recruitment of endogenous anti-carbohydrate antibodies to tumor cells. Chembiochem 15: 1393-1398. doi: 10.1002/cbic.201402019
    [19] Shaw SM, Middleton J, Wigglesworth K, et al. (2019) AGI-134: a fully synthetic α-Gal glycolipid that converts tumors into in situ autologous vaccines, induces anti-tumor immunity and is synergistic with an anti-PD-1 antibody in mouse melanoma models. Cancer Cell Int 19: 346. doi: 10.1186/s12935-019-1059-8
    [20] Dotan N, Altstock RT, Schwarz M, et al. (2006) Anti-glycan antibodies as biomarkers for diagnosis and prognosis. Lupus 15: 442-450. doi: 10.1191/0961203306lu2331oa
    [21] Bello-Gil D, Manez R (2015) Exploiting natural anti-carbohydrate antibodies for therapeutic purposes. Biochemistry Moscow 80: 836-845. doi: 10.1134/S0006297915070044
    [22] Griesemer A, Yamada K, Sykes M (2014) Xenotransplantation: immunological hurdles and progress toward tolerance. Immunol Rev 258: 241-258. doi: 10.1111/imr.12152
    [23] Oyelaran O, McShane LM, Dodd L, et al. (2009) Profiling human serum antibodies with a carbohydrate antigen microarray. J Proteome Res 8: 4301-4310. doi: 10.1021/pr900515y
    [24] Galanina OE, Mecklenburg M, Nifantiev NE, et al. (2003) GlycoChip: multiarray for the study of carbohydrate-binding proteins. Lab Chip 3: 260-265. doi: 10.1039/b305963d
    [25] Shilova N, Navakouski M, Khasbiullina N, et al. (2012) Printed glycan array: antibodies as probed in undiluted serum and effects of dilution. Glycoconjugate J 29: 87-91. doi: 10.1007/s10719-011-9368-8
    [26] Yu PB, Holzknecht ZE, Bruno D, et al. (1996) Modulation of natural IgM binding and complement activation by natural IgG antibodies: a role for IgG anti-Gal alpha1-3Gal antibodies. J Immunol 157: 5163-5168.
    [27] Korchagina EY, Henry SM (2015) Synthetic glycolipid-like constructs as tools for glycobiology research, diagnostics, and as potential therapeutics. Biochemistry Moscow 80: 857-871. doi: 10.1134/S0006297915070068
    [28] Perry H, Bovin N, Henry S (2019) A standardized kodecyte method to quantify ABO antibodies in undiluted plasma of patients before ABO-incompatible kidney transplantation. Transfusion 59: 2131-2140.
    [29] Henry SM, Bovin NV (2018) Kode Technology—a universal cell surface glycan modification technology. J R Soc N Z 49: 100-113. doi: 10.1080/03036758.2018.1546195
    [30] Henry S, Williams E, Barr K, et al. (2018) Rapid one-step biotinylation of biological and non-biological surfaces. Sci Rep 8: 2845. doi: 10.1038/s41598-018-21186-3
    [31] Downes KA, Shulman IA (2014) Pretransfusion testing. Technical Manual Bethesda: American Association of Blood Banks, 371.
    [32] Romano EL, Mollison PL (1973) Mechanism of red cell agglutination by IgG antibodies. Vox Sang 25: 28-31. doi: 10.1159/000460518
    [33] Obukhova P, Tsygankova S, Chinarev A, et al. (2020) Are there specific antibodies against Neu5Gc epitopes in the blood of healthy individuals? Glycobiology 30: 395-406. doi: 10.1093/glycob/cwz107
    [34] Obukhova P, Korchagina E, Henry S, et al. (2012) Natural anti-A and anti-B of the ABO system: allo- and autoantibodies have different epitope specificity. Transfusion 52: 860-869. doi: 10.1111/j.1537-2995.2011.03381.x
    [35] Barr K, Korchagina E, Ryzhov I, et al. (2014) Mapping the fine specificity of ABO monoclonal reagents with A and B type-specific FSL constructs in kodecytes and inkjet printed on paper. Transfusion 54: 2477-2484. doi: 10.1111/trf.12661
    [36] Williams E, Korchagina E, Frame T, et al. (2016) Glycomapping the fine specificity of monoclonal and polyclonal Lewis antibodies with type-specific Lewis kodecytes and function-spacer-lipid constructs printed on paper. Transfusion 56: 325-333. doi: 10.1111/trf.13384
    [37] Hult AK, Frame T, Chesla S, et al. (2012) Flow cytometry evaluation of red blood cells mimicking naturally occurring ABO subgroups after modification with variable amounts of function-spacer-lipid A and B constructs. Transfusion 52: 247-251. doi: 10.1111/j.1537-2995.2011.03268.x
    [38] Henry S (2009) Modification of red blood cells for laboratory quality control use. Curr Opin Hematol 16: 467-472. doi: 10.1097/MOH.0b013e328331257e
    [39] Sneath JS, Sneath PHA (1955) Transformation of the Lewis groups of human red cells. Nature 176: 172. doi: 10.1038/176172a0
    [40] Thorpe SJ, Fox B, Sharp G, et al. (2016) A WHO reference reagent to standardize haemagglutination testing for anti-A and anti-B in serum and plasma: international collaborative study to evaluate a candidate preparation. Vox Sang 111: 161-170. doi: 10.1111/vox.12399
    [41] Bentall A, Barnett NR, Braitch M, et al. (2016) Clinical outcomes with ABO antibody titer variability in a multicenter study of ABO-incompatible kidney transplantation in the United Kingdom. Transfusion 56: 2668-2679. doi: 10.1111/trf.13770
    [42] Kurtenkov O, Klaamas K, Rittenhouse-Olson K, et al. (2005) IgG immune response to tumor-associated carbohydrate antigens (TF, Tn, alphaGal) in patients with breast cancer: impact of neoadjuvant chemotherapy and relation to the survival. Exp Oncol 27: 136-140.
    [43] Strobel E (2008) Hemolytic transfusion reactions. Transfus Med Hemother 35: 346-353. doi: 10.1159/000154811
    [44] McMorrow IM, Comrack CA, Nazarey PP, et al. (1997) Relationship between ABO blood group and levels of Gal α,3Galactose-reactive human immunoglobulin G. Transplantation 64: 546-549. doi: 10.1097/00007890-199708150-00032
    [45] Barreau N, Blancho G, Boulet C, et al. (2000) Natural anti-Gal antibodies constitute 0.2% of intravenous immunoglobulin and are equally retained on a synthetic disaccharide column or on an immobilized natural glycoprotein. Transplant Proc 32: 882-883. doi: 10.1016/S0041-1345(00)01023-X
    [46] Obukhova P, Rieben R, Bovin N (2007) Normal human serum contains high levels of anti-Galα1-4GlcNAc antibodies. Xenotransplantation 14: 627-635. doi: 10.1111/j.1399-3089.2007.00436.x
    [47] Galili U, Korkesh A, Kahane I, et al. (1983) Demonstration of a natural antigalactosyl IgG antibody on thalassemic red blood cells. Blood 61: 1258-1264. doi: 10.1182/blood.V61.6.1258.1258
    [48] GalilI U, Macher BA, Buehler J, et al. (1985) Human natural anti-α-galactosyl IgG. II. The specific recognition of α(1 → 3)-linked galactose residues. J Exp Med 162: 573-582. doi: 10.1084/jem.162.2.573
    [49] Mujahid A, Dickert FL (2015) Blood group typing: from classical strategies to the application of synthetic antibodies generated by molecular imprinting. Sensors 16: 51. doi: 10.3390/s16010051
    [50] Oliver C, Blake D, Henry S (2011) Modeling transfusion reactions and predicting in vivo cell survival with kodecytes. Transfusion 51: 1723-1730. doi: 10.1111/j.1537-2995.2010.03034.x
    [51] Heathcote D, Carroll T, Wang J, et al. (2010) Novel antibody screening cells, MUT+Mur kodecytes, created by attaching peptides onto red blood cells. Transfusion 50: 635-641. doi: 10.1111/j.1537-2995.2009.02480.x
    [52] Henry SM, Komarraju S, Heathcote D, et al. (2011) Designing peptide-based FSL constructs to create Miltenberger kodecytes. ISBT Sci Ser 6: 306-312. doi: 10.1111/j.1751-2824.2011.01505.x
  • Reader Comments
  • © 2020 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0)
通讯作者: 陈斌, bchen63@163.com
  • 1. 

    沈阳化工大学材料科学与工程学院 沈阳 110142

  1. 本站搜索
  2. 百度学术搜索
  3. 万方数据库搜索
  4. CNKI搜索

Metrics

Article views(315) PDF downloads(16) Cited by(0)

Article outline

Figures and Tables

Figures(2)  /  Tables(5)

/

DownLoad:  Full-Size Img  PowerPoint
Return
Return

Catalog