Antibodies to adhesion molecules inhibit the lytic function of MHC-unrestricted cytotoxic cells by preventing their activation

Zarcone, Daniela; Viale, Oriane; Cerruti, Giannamaria; Tenca, Claudya; Malorni, Walter; Arancia, Giuseppe; Iosi, Francesca; Galandrini, Ricciarda; Velardi, Andrea; Moretta, Alessandro; Grossi, Carlo E.

doi:10.1016/0008-8749(92)90035-n

Cited by 31 publications

(21 citation statements)

References 41 publications

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“…The C218 hybridoma cell line (producing the anti-CD56 mAb) was kindly provided by Dr. A. Moretta (Institute Gaslini, Italy) (15). Hybridoma cells were cultured in RPMI medium supplemented with 5% fetal calf serum in a miniPERM bioreactor (Sarsted).…”

Section: Antibodymentioning

confidence: 99%

In Vivo Imaging of Natural Killer Cell Trafficking in Tumors

et al. 2015

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Natural killer cells (NKs) are important effectors of the innate immune system, with marked antitumor activity. Imaging NK trafficking in vivo may be relevant to following up the efficacy of new therapeutic approaches aiming at increasing tumor-infiltrating NKs (TINKs). The specific aims of present study were to efficiently target NKs using a 99m Tc-anti-CD56 and to image human NK trafficking in SCID mice bearing human cancer. Methods: The anti-CD56 monoclonal antibody (mAb) was radiolabeled with 99m Tc, and in vitro quality controls were performed to test labeling efficiency, stability, and binding affinity to CD56. In vivo biodistribution was determined by injecting 5.5 MBq (104 ng) of radiolabeled antibody in the tail vein of SCID mice, which were then sacrificed at 1, 3, 6, and 24 h after injection. Targeting experiments were performed on 2 groups of SCID mice inoculated subcutaneously with increasing numbers of human NKs in the right thigh (from 2.5 · 10 6 to 40 · 10 6 ) and human granulocytes (CD56 − ) or anaplastic thyroid cancer (ARO) cells in the contralateral thigh as control. TINK trafficking imaging was achieved by injecting 5.5 MBq of 99m Tc-anti-CD56 mAb in SCID mice bearing ARO tumor xenografts in the right thigh, 24 h after being reconstituted with 10 5 , 10 6 , or 10 7 human NKs. Results: Anti-CD56 mAb was radiolabeled, achieving a radiochemical purity of more than 97% and a specific activity of 3,700 MBq/mg and retaining biochemical integrity and binding activity. In vivo studies revealed physiologic uptake in the liver and kidneys. Targeting experiments confirmed the specificity of labeled antibody to CD56 1 cells. Human NK cells injected in CD1 nude mice accumulated in the ARO tumors within 24 h and were imaged as early as 3 h after intravenous administration of 99m Tcanti-CD56. Conclusion: 99m Tc-anti-CD56 is a promising tool for in vivo imaging of TINK cell trafficking.

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Section: Antibodymentioning

confidence: 99%

In Vivo Imaging of Natural Killer Cell Trafficking in Tumors

et al. 2015

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“…This chain of events is promoted by the redistribution of killer cell surface structures that polarize toward the TC, an event considered of crucial importance in the NK-TC pairing formation (3). The recruitment and migration of NK cells from blood vessels into target tissues are also in fact piloted by the polarized localization of surface and cytoplasmic molecules (3,4). This remodeling is supervised by cytoskeletal components, which are able to: 1) drive killer cell migration and locomotion; 2) influence their binding activity toward the TC; 3) regulate conjugate formation; and, finally, 4) modulate the killing efficiency.…”

mentioning

confidence: 99%

The Rac-Activating Toxin Cytotoxic Necrotizing Factor 1 Oversees NK Cell-Mediated Activity by Regulating the Actin/Microtubule Interplay

Malorni

Quaranta

Straface

et al. 2003

The Journal of Immunology

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The cell cytoskeleton is widely acknowledged as a master for NK cell function. Specifically, actin filaments guide the NK cell binding to target cells, engendering the formation of the so-called immunological synapse, while microtubules direct the killer behavior. All these cytoskeleton-dependent activities are competently governed by the Rho GTPases, a family of regulatory molecules encompassing the three different subfamilies, Rho, Rac, and Cdc42. By using a Rac GTPase-activating bacterial protein toxin from Escherichia coli named cytotoxic necrotizing factor 1 (CNF1), we obtained results supporting the activation of Rac GTPase as a booster for effector cell-binding efficiency, recruitment ability, and, consequently, cytotoxicity. In particular, the augmented killer capacity of CNF1-treated NK cells was associated with the increased expression of certain cell adhesion or activation-associated molecules and the reshaping of the actin and microtubule networks. Importantly, CNF1 counteracted the activity exerted by toxins disrupting the cytoskeletal architecture. Hence, the activation of Rho GTPases, particularly Rac, induced by CNF1, appears to orchestrate a dynamic cross talk between microtubules and actin filaments, leading to a fruitful NK cell activity and polarization state. Our findings suggest that protein toxins might be viewed as modulators of NK cell cytotoxic activity and could possibly be regarded as useful pharmacological tools for certain Rho-linked immune diseases in the near future.

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“…The CAM also act as costimulating surface molecules, leading to activation of MHC-unrestricted cytolysis [24], As mentioned before, in none of the five lines tested, LFA-3 was upregulated by IFN. Although the exact signif icance of this non-inducibility is not clear, it is tempting to argue that it may have evolutionary significance.…”

Section: Discussionmentioning

confidence: 94%

Defective Expression of Adhesion Molecules on Human Bladder Tumour and Human Tumour Cell Lines

Nouri

Hussain²,

Santos³

et al. 1996

Urol Int

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The pattern of expression of cell adhesion molecules, i.e., leucocyte function associated antigen 3 (LFA-3) and intercellular adhesion molecule 1 (ICAM-1) on human bladder tumour biopsy specimens was investigated. Attempts were also made to study the pattern of induction of these molecules by established human cell lines in response to cytokines. The results indicated that 15 of 25 tumour biopsy specimens were negative for ICAM-1, and amongst the remaining 10, only 1 showed strong positivity, whilst LFA-3 was expressed in 21 of 23 cases. Unlike LFA-3, the pattern of ICAM-1 expression on established tumour cell lines was different in that there were 7 of 21 cases showing positive staining. The parallel investigation of ICAM-1 and major histocompatibility complex class II antigen expression on bladder tumours showed that in 11 of 18 cases, there was a concomitant expression or complete absence of these molecules. In the remaining 7, there were 6 cases where only class II expression was observed. Exposure of cell lines to interferons alpha or gamma had no effects on LFA-3 expression. In contrast, interferon gamma induced ICAM-1 on all the eight lines with constitutive ICAM-1 expression, whereas interferon alpha upregulated only 2 of these 8 lines. The mean ± SD values for ICAM-1 expression on the eight inducible lines were 617 ± 406 cpm before and 943 ± 471 cpm (p = 0.001) after interferon gamma stimulation. The pattern of ICAM-1 inducibility of a bladder cell line Fen to interferon remained unchanged following transfection of a β₂-microglobulin gene and correction of cell surface HLA class I antigens. These results indicate that there was a significant minority of bladder tumours and tumour cell lines with abnormal cell adhesion molecule expression. In some cases, the abnormality in cell lines could not be corrected by cytokine stimulation. It is possible that these abnormalities may play a critical role in the overall tumour strategy for escape from immunological detection.

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Antibodies to adhesion molecules inhibit the lytic function of MHC-unrestricted cytotoxic cells by preventing their activation

Cited by 31 publications

References 41 publications

In Vivo Imaging of Natural Killer Cell Trafficking in Tumors

In Vivo Imaging of Natural Killer Cell Trafficking in Tumors

The Rac-Activating Toxin Cytotoxic Necrotizing Factor 1 Oversees NK Cell-Mediated Activity by Regulating the Actin/Microtubule Interplay

Defective Expression of Adhesion Molecules on Human Bladder Tumour and Human Tumour Cell Lines

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