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104. The molecular bases of Delta/Alpha beta T cell-mediated antigen recognition.

Author

Pellicci, D.G., primary, Uldrich, A.P., additional, Le Nours, J., additional, Ross, F., additional, Chabrol, E., additional, Eckle, S.B.G., additional, de Boer, R., additional, Lim, R.T., additional, McPherson, K., additional, Besra, G., additional, Howell, A.R., additional, Moretta, L., additional, McCluskey, J., additional, Heemskerk, M.H.M., additional, Gras, S., additional, Rossjohn, J., additional, and Godfrey, D.I., additional

Published
2014
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106. Recognition of adult and pediatric acute lymphoblastic leukemia blasts by natural killer cells

Author

Torelli, G. F., primary, Peragine, N., additional, Raponi, S., additional, Pagliara, D., additional, De Propris, M. S., additional, Vitale, A., additional, Bertaina, A., additional, Barberi, W., additional, Moretta, L., additional, Basso, G., additional, Santoni, A., additional, Guarini, A., additional, Locatelli, F., additional, and Foa, R., additional

Published
2014
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111. HLA-G is a component of the chronic lymphocytic leukemia escape repertoire to generate immune suppression: impact of the HLA-G 14 base pair (rs66554220) polymorphism

Author

Rizzo, R., primary, Audrito, V., additional, Vacca, P., additional, Rossi, D., additional, Brusa, D., additional, Stignani, M., additional, Bortolotti, D., additional, D'Arena, G., additional, Coscia, M., additional, Laurenti, L., additional, Forconi, F., additional, Gaidano, G., additional, Mingari, M. C., additional, Moretta, L., additional, Malavasi, F., additional, and Deaglio, S., additional

Published
2013
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117. Dual-functional capability of CD3 +CD56 + CIK cells, a T-cell subset that acquires NK function and retains TCR-mediated specific cytotoxicity

Author

Pievani, A, Borleri, G, Pende, D, Moretta, L, Rambaldi, A, Golay, J, Introna, M, PIEVANI, ALICE SILVIA, Introna, M., Pievani, A, Borleri, G, Pende, D, Moretta, L, Rambaldi, A, Golay, J, Introna, M, PIEVANI, ALICE SILVIA, and Introna, M.

Abstract

CD3 +CD56 + cytokine-induced killer (CIK) cells display a potent cytolytic activity. The adhesion molecule lymphocyte function-associated antigen-1 plays a crucial role in binding as well as in cytolytic activity of CIK cells against tumor target cells expressing the corresponding ligands. CIK cells express activating natural killer (NK) receptors, including NKG2D, DNAX accessory molecule-1 (DNAM-1), and low levels of NKp30. Cell signaling not only through TCR/CD3 but also through NKG2D, DNAM-1, and NKp30 leads to CIK cell activation resulting in granule exocytosis, cytokine secretion, and cytotoxicity. Antibody blocking experiments showed that DNAM-1, NKG2D, and NKp30 are involved in the TCR-independent tumor cell recognition and killing. Anti-CMV-specific CIK cells could be expanded in standard CIK cultures and mediate both specific, MHC-restricted recognition and TCR-independent NK-like cytolytic activity against leukemic cell lines or fresh leukemic blasts. Antibody blocking of lymphocyte function-associated antigen-1 and DNAM-1 led to significant reduction of both CTL and NK-cell functions, whereas blocking of NKG2D and NKp30 only inhibited NK-like cytotoxicity. Their dual-effector function suggests that CIK cells, when used in a clinical setting, may control both neoplastic relapses and viral infections, 2 frequently associated complications in patients who received a transplant. © 2011 by The American Society of Hematology.

Published
2011

119. Natural killer alloeffector responses in haploidentical hemopoietic stem cell transplantation to treat high-risk leukemias

Author

Moretta, L, Locatelli, Franco, Pende, D, Mingari, M C, Moretta, A, Locatelli, F (ORCID:0000-0002-7976-3654), Moretta, L, Locatelli, Franco, Pende, D, Mingari, M C, Moretta, A, and Locatelli, F (ORCID:0000-0002-7976-3654)

Abstract

Natural killer (NK) cells, a major cell type of the innate immunity, express surface receptors that regulate potent effector functions such as cytolytic activity and release of cytokines playing a central role in inflammatory response and immunoregulation. In this contribution, we briefly outline the major steps from the discovery of human leukocyte antigen (HLA)-class I-specific inhibitory receptors in humans to recent successful clinical applications in the cure of high-risk leukemias both in adults and in pediatric patients. A central role is played by 'alloreactive' NK cells originated from donor's CD 34+ cells in eradicating leukemic cells in the setting of T-cell-depleted haploidentical hemopoietic stem cell transplantation. Because alloreactive NK cells play a central role also in preventing graft rejection and graft- vs-host disease, they may represent an ideal tool to treat patients affected by acute high-risk leukemias.

Published
2010

120. Activating and inhibitory killer immunoglobulin-like receptors (KIR) in haploidentical haemopoietic stem cell transplantation to cure high-risk leukaemias

Author

Moretta, A, Pende, D, Locatelli, Franco, Moretta, L, Locatelli, F (ORCID:0000-0002-7976-3654), Moretta, A, Pende, D, Locatelli, Franco, Moretta, L, and Locatelli, F (ORCID:0000-0002-7976-3654)

Abstract

A number of experimental studies have shown that natural killer (NK) cells can eliminate cancer cells and the mechanisms involved in this effect have been uncovered during the last two decades. Clinical data from haploidentical haematopoietic stem cell transplantation (haplo-HSCT) revealed that NK cells were responsible for remarkably favourable effects in both adult and paediatric high-risk leukaemias. NK receptors specific for major histocompatibility complex (MHC) class I molecules, including killer immunoglobulin (Ig)-like receptors (KIR) and CD94/NKG2A, play a major role in the anti-leukaemia effect ( mediating either inhibitory or activating signals). Haplo-HSCT requires a heavy conditioning regimen for the patient and the use of large numbers of T cell-depleted HSC to be grafted. After transplantation, natural killer cells develop from HSC shortly after engraftment and may include 'alloreactive' NK cells that kill leukaemic cells and prevent graft-versus-host disease (GvHD). Alloreactive NK cells are characterized by the expression of KIR that are not engaged by any of the human leucocyte antigen (HLA) class I alleles expressed by the patient. Their generation is dependent upon the existence of a KIR/HLA class I mismatch between donor and recipient. Novel important information on the function and specificity of different KIR has been obtained recently by the analysis of donor-derived alloreactive NK cells in a cohort of paediatric patients given haplo-HSCT to cure acute, high-risk leukaemias.

Published
2009

121. Unsung hero Robert C. Gallo

Author

Abbadessa, G., Accolla, R., Aiuti, F., Albini, A., Aldovini, A., Alfano, M., Antonelli, G., Bartholomew, C., Bentwich, Z., Bertazzoni, U., Berzofsky, J., Biberfeld, P., Boeri, E., Buonaguro, L., Buonaguro, F., Bukrinsky, M., Burny, A., Caruso, A., Cassol, S., Chandra, P., Ceccherini-Nelli, L., Chieco-Bianchi, L., Clerici, M., Colombini-Hatch, S., Morghen, C., De Maria, A., De Rossi, A., Dierich, M., Della-Favera, R., Dolei, A., Douek, D., Erfle, V., Felber, B., Fiorentini, S., Franchini, G., Gershoni, J., Gotch, F., Green, P., Greene, W., Hall, W., Haseltine, W., Jacobson, S., Kallings, L., Kalyanaraman, V., Katinger, H., Khalili, K., Klein, G., Klein, E., Klotman, M., Klotman, P., Kotler, M., Kurth, R., Lafeuillade, A., La Placa, M., Lewis, J., Lillo, F., Lisziewicz, J., Lomonico, A., Lopalco, L., Lori, F., Lusso, P., Macchi, B., Malim, M., Margolis, L., Markham, P., Mcclure, M., Miller, N., Mingari, M., Moretta, L., Noonan, D., O'Brien, S., Okamoto, T., Pal, R., Palese, P., Panet, A., Pantaleo, G., Pavlakis, G., Pistello, M., Plotkin, S., Poli, G., Pomerantz, R., Radaelli, A., Robert-Guroff, M., Roederer, M., Sarngadharan, M., Schols, D., Secchiero, P., Shearer, G., Siccardi, A., Stevenson, M., Svoboda, J., Tartaglia, J., Torelli, G., Tornesello, M., Tschachler, E., Vaccarezza, Mauro, Vallbracht, A., Van Lunzen, J., Varnier, O., Abbadessa, G., Accolla, R., Aiuti, F., Albini, A., Aldovini, A., Alfano, M., Antonelli, G., Bartholomew, C., Bentwich, Z., Bertazzoni, U., Berzofsky, J., Biberfeld, P., Boeri, E., Buonaguro, L., Buonaguro, F., Bukrinsky, M., Burny, A., Caruso, A., Cassol, S., Chandra, P., Ceccherini-Nelli, L., Chieco-Bianchi, L., Clerici, M., Colombini-Hatch, S., Morghen, C., De Maria, A., De Rossi, A., Dierich, M., Della-Favera, R., Dolei, A., Douek, D., Erfle, V., Felber, B., Fiorentini, S., Franchini, G., Gershoni, J., Gotch, F., Green, P., Greene, W., Hall, W., Haseltine, W., Jacobson, S., Kallings, L., Kalyanaraman, V., Katinger, H., Khalili, K., Klein, G., Klein, E., Klotman, M., Klotman, P., Kotler, M., Kurth, R., Lafeuillade, A., La Placa, M., Lewis, J., Lillo, F., Lisziewicz, J., Lomonico, A., Lopalco, L., Lori, F., Lusso, P., Macchi, B., Malim, M., Margolis, L., Markham, P., Mcclure, M., Miller, N., Mingari, M., Moretta, L., Noonan, D., O'Brien, S., Okamoto, T., Pal, R., Palese, P., Panet, A., Pantaleo, G., Pavlakis, G., Pistello, M., Plotkin, S., Poli, G., Pomerantz, R., Radaelli, A., Robert-Guroff, M., Roederer, M., Sarngadharan, M., Schols, D., Secchiero, P., Shearer, G., Siccardi, A., Stevenson, M., Svoboda, J., Tartaglia, J., Torelli, G., Tornesello, M., Tschachler, E., Vaccarezza, Mauro, Vallbracht, A., Van Lunzen, J., and Varnier, O.

Published
2009

127. Structural basis for a major histocompatibility complex class Ib-restricted T cell response

Author

Hoare, HL, Sullivan, LC, Pietra, G, Clements, CS, Lee, EJ, Ely, LK, Beddoe, T, Falco, M, Kjer-Nielsen, L, Reid, HH, McCluskey, J, Moretta, L, Rossjohn, J, Brooks, AG, Hoare, HL, Sullivan, LC, Pietra, G, Clements, CS, Lee, EJ, Ely, LK, Beddoe, T, Falco, M, Kjer-Nielsen, L, Reid, HH, McCluskey, J, Moretta, L, Rossjohn, J, and Brooks, AG

Abstract

In contrast to antigen-specific immunity orchestrated by major histocompatibility complex (MHC) class Ia molecules, the ancestrally related nonclassical MHC class Ib molecules generally mediate innate immune responses. Here we have demonstrated the structural basis by which the MHC class Ib molecule HLA-E mediates an adaptive MHC-restricted cytotoxic T lymphocyte response to human cytomegalovirus. Highly constrained by host genetics, the response showed notable fine specificity for position 8 of the viral peptide, which is the sole discriminator of self versus nonself. Despite the evolutionary divergence of MHC class Ia and class Ib molecules, the structure of the T cell receptor-MHC class Ib complex was very similar to that of conventional T cell receptor-MHC class Ia complexes. These results emphasize the evolutionary 'ambiguity' of HLA-E, which not only interacts with innate immune receptors but also has the functional capacity to mediate virus-specific cytotoxic T lymphocyte responses during adaptive immunity.

Published
2006

130. Genotype-phenotype study of familial haemophagocytic lymphohistiocytosis type 3

Author

Sieni, E., primary, Cetica, V., additional, Santoro, A., additional, Beutel, K., additional, Mastrodicasa, E., additional, Meeths, M., additional, Ciambotti, B., additional, Brugnolo, F., additional, zur Stadt, U., additional, Pende, D., additional, Moretta, L., additional, Griffiths, G. M., additional, Henter, J.-I., additional, Janka, G., additional, and Arico, M., additional

Published
2011
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134. Use of anti-CD3 and anti-CD16 bispecific monoclonal antibodies for the targeting of T and NK cells against tumor cells

Author

Ferrini, S., Cambiaggi, A., Sforzini, S., Canevari, S., Delia Mezzanzanica, Colnaghi, M. I., and Moretta, L.

Subjects
ErbB Receptors, Killer Cells, Natural, CD3 Complex, Neoplasms, T-Lymphocytes, Antibodies, Bispecific, Receptors, IgG, Tumor Cells, Cultured, Antibodies, Monoclonal, Humans, Immunotherapy, Adoptive, Cells, Cultured
Abstract

To target T lymphocytes against EGF-R+ tumors, we constructed anti-CD3/anti-EGF-R bimAbs either by the generation of a hybrid hybridoma (quadroma) or by a chemical cross-linking method. Analysis of the in vitro functional activity of these two different constructs indicated that the quadroma-secreted bimAb was more efficient in targeting the CD3+8+ clones against EGF-R+ target cells with respect to the bimAb produced by chemical method. In addition, the quadroma-produced bimAb is able to induce cytolysis of EGF-R+ tumor cell lines of PHA-induced lymphoblasts that had been expanded in IL-2-containing medium, whereas tumor cells lacking expression of EGF-R were not lysed. Resting PBL targeted by the bimAb did not display significant cytotoxicity against the relevant tumor. An anti-CD16 hybridoma (IgG1) was fused with an anti-folate-binding protein hybrid (IgG2a) to construct bimAbs to target NK cells against NK-resistant ovarian carcinomas. The hybrid IgG1/IgG2a bimAb triggered the specific lysis of relevant target cells by resting NK cells, but it was ineffective when CD8+TCR alpha/beta+ cultured cell populations were used as effectors. Only marginal increases of cytolytic activity could be induced by the bimAb when IL-2-activated PBL (i.e., LAK cells) were used as effectors due to the high cytolytic activity of these cells against the relevant tumors in the absence of bimAb. The possible use of anti-CD16 or anti-CD3 bimAbs for the development of different cellular immunotherapy strategies against cancer is discussed.

Published
1993

139. NKp44 expression, phylogenesis and function in non-human primate NK cells

Author

De Maria, A., primary, Ugolotti, E., additional, Rutjens, E., additional, Mazza, S., additional, Radic, L., additional, Faravelli, A., additional, Koopman, G., additional, Di Marco, E., additional, Costa, P., additional, Ensoli, B., additional, Cafaro, A., additional, Mingari, M. C., additional, Moretta, L., additional, Heeney, J., additional, and Biassoni, R., additional

Published
2009
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140. Unsung Hero Robert C. Gallo

Author

Abbadessa, G., primary, Accolla, R., additional, Aiuti, F., additional, Albini, A., additional, Aldovini, A., additional, Alfano, M., additional, Antonelli, G., additional, Bartholomew, C., additional, Bentwich, Z., additional, Bertazzoni, U., additional, Berzofsky, J. A., additional, Biberfeld, P., additional, Boeri, E., additional, Buonaguro, L., additional, Buonaguro, F. M., additional, Bukrinsky, M., additional, Burny, A., additional, Caruso, A., additional, Cassol, S., additional, Chandra, P., additional, Ceccherini-Nelli, L., additional, Chieco-Bianchi, L., additional, Clerici, M., additional, Colombini-Hatch, S., additional, de Giuli Morghen, C., additional, de Maria, A., additional, de Rossi, A., additional, Dierich, M., additional, Della-Favera, R., additional, Dolei, A., additional, Douek, D., additional, Erfle, V., additional, Felber, B., additional, Fiorentini, S., additional, Franchini, G., additional, Gershoni, J. M., additional, Gotch, F., additional, Green, P., additional, Greene, W. C., additional, Hall, W., additional, Haseltine, W., additional, Jacobson, S., additional, Kallings, L. O., additional, Kalyanaraman, V. S., additional, Katinger, H., additional, Khalili, K., additional, Klein, G., additional, Klein, E., additional, Klotman, M., additional, Klotman, P., additional, Kotler, M., additional, Kurth, R., additional, Lafeuillade, A., additional, La Placa, M., additional, Lewis, J., additional, Lillo, F., additional, Lisziewicz, J., additional, Lomonico, A., additional, Lopalco, L., additional, Lori, F., additional, Lusso, P., additional, Macchi, B., additional, Malim, M., additional, Margolis, L., additional, Markham, P. D., additional, Mcclure, M., additional, Miller, N., additional, Mingari, M. C., additional, Moretta, L., additional, Noonan, D., additional, O'Brien, S., additional, Okamoto, T., additional, Pal, R., additional, Palese, P., additional, Panet, A., additional, Pantaleo, G., additional, Pavlakis, G., additional, Pistello, M., additional, Plotkin, S., additional, Poli, G., additional, Pomerantz, R., additional, Radaelli, A., additional, Robertguroff, M., additional, Roederer, M., additional, Sarngadharan, M. G., additional, Schols, D., additional, Secchiero, P., additional, Shearer, G., additional, Siccardi, A., additional, Stevenson, M., additional, Svoboda, J., additional, Tartaglia, J., additional, Torelli, G., additional, Tornesello, M. L., additional, Tschachler, E., additional, Vaccarezza, M., additional, Vallbracht, A., additional, van Lunzen, J., additional, Varnier, O., additional, Vicenzi, E., additional, von Melchner, H., additional, Witz, I., additional, Zagury, D., additional, Zagury, J.-F., additional, Zauli, G., additional, and Zipeto, D., additional

Published
2009
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144. Targeting of T or NK lymphocytes against tumor cells by bispecific monoclonal antibodies: role of different triggering molecules

Author

Silvano Ferrini, Cambiaggi, A., Cantoni, C., Canevari, S., Mezzanzanica, D., Colnaghi, M. I., and Moretta, L.

Subjects
Cytotoxicity, Immunologic, Killer Cells, Natural, Lymphokines, CD3 Complex, Antigens, CD, Neoplasms, T-Lymphocytes, Receptors, Antigen, T-Cell, Antibodies, Monoclonal, Humans
Abstract

MAbs directed against triggering surface molecules expressed by T lymphocytes (CD3, TCR, CD2, CD28) or by NK cells (CD2, CD16) are able to induce the functional program of these cells. These MAbs represent suitable reagents to construct biMAbs directed against TAA, in order to specifically target effector lymphocytes against tumor cells. Anti-CD3/anti-EGF-R biMAbs were constructed to specifically direct T lymphocytes against EGF-R+ tumor cells. Such biMAb are able to induce cytolysis of EGF-R+ tumor cell lines (A431, IGROV, KATO-III and U-87) by cytolytic CD3+ effector lymphocytes while tumor cells having low or absent expression of EGF-R were not lysed. In addition, both cytolytic T (CD8+) cells and non-cytolytic (CD4+) IL-2-expanded lymphocytes were able to secrete lymphokines upon contact with EGF-R+ tumor cells. To target NK cells against NK resistant ovarian carcinomas, we used an anti-CD16 Mab (IgG1) together with an anti-ovarian carcinoma MAb (IgG2a), to construct biMAbs using the hybrid hybridoma technique. The hybrid IgG1/IgG2a biMAb triggered the specific lysis of relevant target cells by resting NK cells and by a subset of NK clones. In addition, some TCR gamma/delta+ clones but not TCR alpha/beta+ clones could be targeted by the biMAb.

Published
1992

149. Human gamma delta T cells that inhibit the in vitro growth of the asexual blood stages of the Plasmodium falciparum parasite express cytolytic and proinflammatory molecules.

Author

Troye-Blomberg, Marita, Worku, S, Tangteerawatana, P, Jamshaid, R, Söderström, K, Elghazali, G, Moretta, L, Hammarström, Marie-Louise, Mincheva-Nilsson, Lucia, Troye-Blomberg, Marita, Worku, S, Tangteerawatana, P, Jamshaid, R, Söderström, K, Elghazali, G, Moretta, L, Hammarström, Marie-Louise, and Mincheva-Nilsson, Lucia

Abstract

The functional properties, regarding parasite growth inhibition in vitro, the cytotoxic potential and cytokine profiles of human gammadelta+ and alphabeta+ T cells, T-cell lines and clones stimulated with Plasmodium falciparum-antigen-or T-cell mitogen in vitro were investigated. Using reverse transcriptase-polymerase chain reaction (RT-PCR) and specific primers, mRNA for the cytolytic molecules perforin, granzyme A and B, Fas and Fas ligand (FasL) were detected in both the gammadelta- and the alphabetaT cells. Despite this fact, only gammadeltaT cells inhibited, both Vdelta1+ and Vdelta2+, the in vitro growth of the asexual blood stages in a dose dependent manner. The inhibition required cell-to-cell contact and was not observed until the second parasite replication implied that the likely gammadeltaT-cell target was the extracellular merozoite or schizont. The failure of alphabetaT cells to inhibit the growth of the parasite suggests requirement of additional cytolytic molecules/signals or different receptor specificities exhibited by the gammadeltaT cells. Both the gammadelta- and alphabetaT cells expressed mRNA for a large number of cytokines. Interferon (IFN)-gamma, interleukin (IL) IL-5, IL-6, IL-8, tumour necrosis factor alpha (TNFalpha), tumour necrosis factor beta (TNF-beta)/lymphotoxin (LT) and T-cell growth factor beta-1 (TGF-beta1) were observed in all activated clones tested. No IL-3 was detected, while IL-1beta, IL-2, IL-4, IL-10 and GM-CSF were variably expressed. In conclusion, our data show that gammadeltaT cells in malaria nonimmune individuals inhibit the asexual blood stages of P. falciparum malaria, while similarly activated alphabetaT cells do not. Thus, it is likely that the gammadeltaT cells could play a mandatory role in the elimination of parasites and/or the regulation of the early immune response to malaria infection.

Published
1999

150. Analysis of natural killer cells isolated from human decidua: evidence that 2B4 (CD244) functions as an inhibitory receptor and blocks NK-cell function

Author

Vacca, P., primary, Pietra, G., additional, Falco, M., additional, Romeo, E., additional, Bottino, C., additional, Bellora, F., additional, Prefumo, F., additional, Fulcheri, E., additional, Venturini, P. L., additional, Costa, M., additional, Moretta, A., additional, Moretta, L., additional, and Mingari, M. C., additional

Published
2006
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