Variations in Activity of the Human Natural Anti-Gal Antibody in Young and Elderly Populations

Wang, Le; Anaraki, Farvardin; Henion, Timothy R.; Galili, Uri

doi:10.1093/gerona/50a.4.m227

Cited by 41 publications

(26 citation statements)

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“…A further advantage for clinical application of this approach is the fact that all humans have natural antibodies against the Gal(␣1,3)Gal epitope, although the proportion of individuals with low affinity anti-Gal antibody increases in the elderly. 28 Immunisation with the sugar epitope is a possible way to increase titres of anti-Gal antibodies if this poses a limitation.…”

Section: Figure 6 Pi-plc Digestion Of Target Cells Ht1080␣ and Nontrmentioning

confidence: 99%

Induction of complement attack on human cells by Gal(alpha1,3)Gal xenoantigen expression as a gene therapy approach to cancer

1999

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Galactose(␣1,3)galactose on the surface of cells of nonfor those cells expressing the antigen in a mixed cell popuprimate organs is the major xenoantigen responsible for lation. The mechanism of cell lysis mimicked that involved hyperacute rejection in xenotransplantation. The antigen is in hyperacute rejection: activation of the classical compsynthesised by (␣1,3)galactosyl transferase. Humans lack lement pathway by natural antibody specific for this enzyme and their serum contains high levels of pregalactose(␣1,3)galactose. The degree of lysis was deterexisting natural antibody which recognises the structure mined by both the level of specific antibody and the and activates complement. We have evaluated in vitro the expression of glycophosphatidylinositol-linked complement potential for delivery of this enzyme to sensitise human regulatory proteins. We conclude that expression of cells to complement attack as a gene therapy approach (␣1,3)galactosyl transferase is a promising new therapeutic to cancer. Retrovirus-mediated delivery of (␣1,3)galactosyl approach for cancer gene therapy, avoiding toxicity probtransferase resulted in high level expression which led to lems associated with application of prodrugs and with the serum-mediated lysis of five human cell targets, including potential to elicit further immunological responses. endothelial and primary melanoma cells. Lysis was specific

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Section: Figure 6 Pi-plc Digestion Of Target Cells Ht1080␣ and Nontrmentioning

confidence: 99%

Induction of complement attack on human cells by Gal(alpha1,3)Gal xenoantigen expression as a gene therapy approach to cancer

1999

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“…It constitutes ~1% of serum Igs in all young and elderly individuals that are not severely immunocompromised (15, 16). Anti-Gal Ab production is elicited as a result of constant antigenic stimulation by gastrointestinal bacteria (17).…”

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confidence: 99%

Rapid Recruitment and Activation of Macrophages by Anti-Gal/α-Gal Liposome Interaction Accelerates Wound Healing

Wigglesworth

Racki

Mishra

et al. 2011

The Journal of Immunology

179

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Macrophages are pivotal in promoting wound healing. We hypothesized that topical application of liposomes with glycolipids that carry Gala1-3Galb1-4GlcNAc-R epitopes (α-gal liposomes) on wounds may accelerate the healing process by rapid recruitment and activation of macrophages in wounds. Immune complexes of the natural anti-Gal Ab (constituting ~1% of Ig in humans) bound to its ligand, the α-gal epitope on α-gal liposomes would induce local activation of complement and generation of complement chemotactic factors that rapidly recruit macrophages. Subsequent binding of the Fc portion of anti-Gal coating α-gal liposomes to FcγRs on recruited macrophages may activate macrophage genes encoding cytokines that mediate wound healing. We documented the efficacy of this treatment in α1,3galactosyltrasferase knockout mice. In contrast to wild-type mice, these knockout mice lack α-gal epitopes and can produce the anti-Gal Ab. The healing time of excisional skin wounds treated with α-gal liposomes in these mice is twice as fast as that of control wounds. Moreover, scar formation in α-gal liposome-treated wounds is much lower than in physiologic healing. Additional sonication of α-gal liposomes resulted in their conversion into submicroscopic α-gal nanoparticles. These α-gal nanoparticles diffused more efficiently in wounds and further increased the efficacy of the treatment, resulting in 95–100% regeneration of the epidermis in wounds within 6 d. The study suggests that α-gal liposome and α-gal nanoparticle treatment may enhance wound healing in the clinic because of the presence of high complement activity and high anti-Gal Ab titers in humans.

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“…We speculated that the complement activation level was the main factor underlying differences in cell death among different ␣-gal-expressing cells. The activation of the complement cascade mediated by ␣-gal is affected by ␣-gal density on the targeted cells, blood type, anti-␣-gal Ab titers, and concentration of complement factors (35,41,63,67). In our study, the Ls-174T-GT, with a higher level of ␣-gal expression than SW620-GT, showed significantly lower sensitivity to CDC compared with SW620-GT.…”

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confidence: 99%

CD55 limits sensitivity to complement-dependent cytolysis triggered by heterologous expression of α-gal xenoantigen in colon tumor cells

Wang

Qin

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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Y. CD55 limits sensitivity to complement-dependent cytolysis triggered by heterologous expression of ␣-gal xenoantigen in colon tumor cells. Am J Physiol Gastrointest Liver Physiol 306: G1056-G1064, 2014. First published April 24, 2014 doi:10.1152/ajpgi.00464.2013.-Engineering cancer cells to express heterologous antigen ␣-gal and induce the destruction of tumor cells depending on the complement cascade may be a promising strategy of tumor therapy. However, the feasibility and effect of using ␣-gal to induce colorectal adenocarcinoma cell line cytolysis is not yet known. In this study, we evaluated ␣-gal expression's ability to sensitize human colorectal adenocarcinoma cell lines to complement attack in cell lines LoVo, SW620, and Ls-174T. Nearly all ␣-gal-expressing LoVo and SW620 cells were killed by normal human serum (NHS), but ␣-gal-expressing Ls-174T cells showed no significant lysis. We analyzed the expression levels of membrane-bound complement regulatory proteins (mCRPs) on the three cell lines, and their protective role in ␣-gal-mediated activation of the complement. LoVo showed no expression of any of the three proteins. CD59 was strongly expressed by SW620 and Ls-174T. CD46 and CD55 varied between the two cell lines. CD46 on SW620 was only half the intensity of CD46 on Ls-174T. Ls-174T showed a notable expression of CD55, while expression of CD55 on SW620 was not detected. The sensitivity of Ls-174T expressing ␣-gal to NHS greatly increased following the downregulation of CD46 and CD55 with short hairpin RNA (shRNA). However, there is no increase in cell killing when CD59 expression was diminished. Our findings suggest that the use of ␣-gal as antigen to induce tumor cell killing may be a potential therapeutic strategy in colon cancer and that CD55 plays a primary role in conferring resistance to lysis. ␣-gal epitope; membrane-bound complement regulatory proteins; complement-dependent cytotoxicity; colorectal carcinoma COLORECTAL CANCER is the third most commonly diagnosed cancer in males and the second in females (28, 57). Surgery is the mainstay of treatment in most cases of colon cancer. Adjuvant therapies, primarily chemotherapy and radiotherapy, have improved the survival rate and quality of life in colorectal cancer patients. However, the 5-yr survival rate remains at ϳ50%, which explains the growing interest in alternative therapies that have no serious side effects and that have the potential to eradicate residual tumors after conventional treatment. A deeper understanding of the interaction between the host immune system and malignant tumors has enabled the development of effective clinical strategies that improve immune responses against tumors. We seek to develop a therapeutic strategy that induces a specific immune response resulting in direct tumor cell killing, depending on the activation of the complement system.

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Variations in Activity of the Human Natural Anti-Gal Antibody in Young and Elderly Populations

Abstract: The proportion of individuals with low affinity anti-Gal increases in the elderly population in comparison with the young population. The possible molecular mechanisms which may result in the age-associated decrease in the antibody affinity are discussed.

Cited by 41 publications

References 0 publications

Induction of complement attack on human cells by Gal(alpha1,3)Gal xenoantigen expression as a gene therapy approach to cancer

Induction of complement attack on human cells by Gal(alpha1,3)Gal xenoantigen expression as a gene therapy approach to cancer

Rapid Recruitment and Activation of Macrophages by Anti-Gal/α-Gal Liposome Interaction Accelerates Wound Healing

CD55 limits sensitivity to complement-dependent cytolysis triggered by heterologous expression of α-gal xenoantigen in colon tumor cells

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