The good and evil of complement activation in HIV-1 infection

Yu, Qigui; Yu, Richard; Qin, Xuebin

doi:10.1038/cmi.2010.8

Cited by 63 publications

(74 citation statements)

References 148 publications

(170 reference statements)

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“…3 CD59, a critical membrane complement regulator, inhibits membrane attack complex formation by binding to the 8a and 9 (C8a and C9) complement proteins. [4][5][6] CD59 is universally expressed in normal cells and highly expressed in many kinds of cancer cells, including NHL and chronic lymphocytic leukemia (CLL). 3 Extensive clinical and experimental evidence indicates that CD59 is highly effective at protecting NHL and CLL cells from Ab (rituximab or ofatumumab)-mediated CDC.…”

Section: Introductionmentioning

confidence: 99%

Application of a novel inhibitor of human CD59 for the enhancement of complement-dependent cytolysis on cancer cells

You

et al. 2011

Cell Mol Immunol

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Many monoclonal antibodies (mAbs) have been extensively used in the clinic, such as rituximab to treat lymphoma. However, resistance and non-responsiveness to mAb treatment have been challenging for this line of therapy. Complement is one of the main mediators of antibody-based cancer therapy via the complement-dependent cytolysis (CDC) effect. CD59 plays a critical role in resistance to mAbs through the CDC effect. In this paper, we attempted to investigate whether the novel CD59 inhibitor, recombinant ILYd4, was effective in enhancing the rituximab-mediated CDC effect on rituximab-sensitive RL-7 lymphoma cells and rituximab-induced resistant RR51.2 cells. Meanwhile, the CDC effects, which were mediated by rituximab and anti-CD24 mAb, on the refractory multiple myeloma (MM) cell line ARH-77 and the solid tumor osteosarcoma cell line Saos-2, were respectively investigated. We found that rILYd4 rendered the refractory cells sensitive to the mAb-mediated CDC effect and that rILYd4 exhibited a synergistic effect with the mAb that resulted in tumor cells lysis. This effect on tumor cell lysis was apparent on both hematological tumors and solid tumors. Therefore, rILYd4 may serve as an adjuvant for mAb mediated-tumor immunotherapy. Keywords: CD59; complement; lymphoma; multiple myeloma; rituximab INTRODUCTIONMonoclonal antibody (mAb) therapy is becoming a powerful approach and is increasingly used in the clinic for the treatment of different types of cancer through targeting specific cancer antigens. Rituximab, the first mAb approved for cancer therapy by the Food and Drug Administration, has been successfully used in the treatment of B-cell non-Hodgkin's B-lymphoma (NHL) via specifically targeting the CD20 molecule on the B lymphocyte membrane. Treatment with rituximab has lead to greatly improved clinical outcomes. 1 Trastuzumab (Herceptin) is used to treat HER2-positive breast cancer. Other new mAbs are actively being developed. Once the antibodies (Abs) are given, they can then recruit other parts of the immune system to destroy the cancer cells or to enhance the immune response against the cancer. The mechanism of action of these Abs and the host and cellular factors that influence the immune response following Ab treatment are not completely known. The induction of apoptosis, Abdependent cell cytotoxicity and complement-mediated cell death (CDC) are the proposed mechanisms of action of these Abs. 2 Complement is one of the main mediators of Ab-based cancer therapy via the CDC effect. When cancer therapeutic Abs activate the so-called classical complement pathway, they trigger the formation of the membrane attack complex on cancer cells, leading to the killing of cancer cells through CDC. 3 CD59, a critical membrane complement regulator, inhibits membrane attack complex formation by binding to

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Section: Introductionmentioning

confidence: 99%

Application of a novel inhibitor of human CD59 for the enhancement of complement-dependent cytolysis on cancer cells

You

et al. 2011

Cell Mol Immunol

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“…Lytic MAC formation results in colloidoosmotic swelling and lysis of the target (Mayer, 1984;Yu et al, 2010). Normally, MAC attacks homologous nucleated cells mainly through sublytic MAC because nucleated cells possess several protective mechanisms against the cytolytic effect of the MAC, including CD59, antiapoptotic genes and endocytosis/shedding of MAC Zhou et al, 2008).…”

Section: Mac Functionmentioning

confidence: 99%

“…The complement system consists of about 30 soluble and membrane-bound proteins, and is activated by three distinct pathways: classical, mannose-binding lectin (MBL) and alternative pathways, either on pathogen surfaces or in plasma (Yu et al, 2010;Zhou et al, 2008). Activation of these pathways depends on different molecules for their initiation (Qin and Gao, 2006;Zhou et al, 2008).…”

Section: Complement Activationmentioning

confidence: 99%

“…To prevent the potentially harmful effect of complement activation on autologous cells, about 10 plasma-and membrane-bound inhibitory proteins have evolved to restrict complement activation at different stages of activation pathways (Yu et al, 2010;Zhou et al, 2008). The soluble plasma complement regulatory proteins include C1 inhibitor, which regulates C1; factor H and factor I, which regulate the cleavage of C3b and C3/C5 convertases; C4 binding protein, which splits C4 convertase and assists factor I in the cleavage of C4b; and S-protein, clusterin, and serum lipids, which compete with membrane lipids to react with nascent C5b67 (Yu et al, 2010;Zhou et al, 2008).…”

Section: Complement Regulationmentioning

confidence: 99%

“…The soluble plasma complement regulatory proteins include C1 inhibitor, which regulates C1; factor H and factor I, which regulate the cleavage of C3b and C3/C5 convertases; C4 binding protein, which splits C4 convertase and assists factor I in the cleavage of C4b; and S-protein, clusterin, and serum lipids, which compete with membrane lipids to react with nascent C5b67 (Yu et al, 2010;Zhou et al, 2008). Moreover, three membrane proteins that are expressed on the surface of almost all cell types inhibit autologous complement activation, thereby protecting self cells from complement-mediated injury (Morgan, 1999).…”

Section: Complement Regulationmentioning

confidence: 99%

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