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Previous Volume 333:1038-1044 October 19, 1995 Number 16 Next

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ABSTRACT

Background Cytomegalovirus (CMV) disease in immunocompromised patients correlates with a deficiency of CD8+ cytotoxic T lymphocytes specific for CMV. We evaluated the safety and immunologic effects of immunotherapy with clones of these lymphocytes in recipients of allogeneic bone marrow transplants.

Methods Clones of CD8+ cytotoxic T cells specific for CMV proteins were isolated from the blood of bone marrow donors. Fourteen patients each received four intravenous infusions of these clones from their donors beginning 30 to 40 days after marrow transplantation. The reconstitution of cellular immunity against CMV was monitored before and during the period of infusions and for up to 12 weeks after the final infusion. The rearranged genes encoding the T-cell receptor served as markers in evaluating the persistence of the transferred T cells.

Results No toxic effects related to the infusions were observed. Cytotoxic T cells specific for CMV were reconstituted in all patients. In vitro measurements showed that cytotoxic activity against CMV was significantly increased (P<0.001) after the infusions in 11 patients who were deficient in such activity before therapy. The level of activity achieved after the infusions was similar to that measured in the donors. Analysis of rearranged T-cell–receptor genes in T cells obtained from two recipients indicated that the transferred clones persisted for at least 12 weeks. Cytotoxic-T-cell activity declined in patients deficient in CD4+ T-helper cells specific for CMV, suggesting that helper-T-cell function is needed for the persistence of transferred CD8+ T cells. Neither CMV viremia nor CMV disease developed in any of the 14 patients.

Conclusions The transfer of CMV-specific clones of CD8+ T cells derived from the bone marrow donor is a safe and effective way to reconstitute cellular immunity against CMV after allogeneic marrow transplantation.

Source Information

From the Fred Hutchinson Cancer Research Center (E.A.W., P.D.G., M.J.G., K.S.W., E.D.T., S.R.R.) and the Departments of Immunology (P.D.G., R.J.F.) and Medicine (P.D.G., E.D.T., S.R.R.), University of Washington, Seattle.

Address reprint requests to Dr. Riddell at the Fred Hutchinson Cancer Research Center, Mailstop M758, 1124 Columbia St., Seattle, WA 98104.

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Anticytomegalovirus T-Cell Clones
Locatelli F., Maccario R., Gerna G., Walter E. A., Greenberg P. D., Riddell S. R.
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N Engl J Med 1996; 334:601, Feb 29, 1996. Correspondence

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• Torikai, H., Akatsuka, Y., Miyazaki, M., Warren, E. H. III, Oba, T., Tsujimura, K., Motoyoshi, K., Morishima, Y., Kodera, Y., Kuzushima, K., Takahashi, T. (2004). A Novel HLA-A*3303-Restricted Minor Histocompatibility Antigen Encoded by an Unconventional Open Reading Frame of Human TMSB4Y Gene. J. Immunol. 173: 7046-7054 [Abstract] [Full Text]  
• Weekes, M. P., Wills, M. R., Sissons, J. G. P., Carmichael, A. J. (2004). Long-Term Stable Expanded Human CD4+ T Cell Clones Specific for Human Cytomegalovirus Are Distributed in Both CD45RAhigh and CD45ROhigh Populations. J. Immunol. 173: 5843-5851 [Abstract] [Full Text]  
• Chang, W. L. W., Baumgarth, N., Yu, D., Barry, P. A. (2004). Human Cytomegalovirus-Encoded Interleukin-10 Homolog Inhibits Maturation of Dendritic Cells and Alters Their Functionality. J. Virol. 78: 8720-8731 [Abstract] [Full Text]  
• Manley, T. J., Luy, L., Jones, T., Boeckh, M., Mutimer, H., Riddell, S. R. (2004). Immune evasion proteins of human cytomegalovirus do not prevent a diverse CD8+ cytotoxic T-cell response in natural infection. Blood 104: 1075-1082 [Abstract] [Full Text]  
• Wang, Z., La Rosa, C., Mekhoubad, S., Lacey, S. F., Villacres, M. C., Markel, S., Longmate, J., Ellenhorn, J. D. I., Siliciano, R. F., Buck, C., Britt, W. J., Diamond, D. J. (2004). Attenuated poxviruses generate clinically relevant frequencies of CMV-specific T cells. Blood 104: 847-856 [Abstract] [Full Text]  
• Parkhurst, M. R., Riley, J. P., Igarashi, T., Li, Y., Robbins, P. F., Rosenberg, S. A. (2004). Immunization of Patients with the hTERT:540-548 Peptide Induces Peptide-Reactive T Lymphocytes That Do Not Recognize Tumors Endogenously Expressing Telomerase. Clin. Cancer Res. 10: 4688-4698 [Abstract] [Full Text]  
• Blattman, J. N., Greenberg, P. D. (2004). Cancer Immunotherapy: A Treatment for the Masses. Science 305: 200-205 [Abstract] [Full Text]  
• Kotloff, R. M., Ahya, V. N., Crawford, S. W. (2004). Pulmonary Complications of Solid Organ and Hematopoietic Stem Cell Transplantation. Am. J. Respir. Crit. Care Med. 170: 22-48 [Abstract] [Full Text]  
• Senechal, B., Boruchov, A. M., Reagan, J. L., Hart, D. N. J., Young, J. W. (2004). Infection of mature monocyte-derived dendritic cells with human cytomegalovirus inhibits stimulation of T-cell proliferation via the release of soluble CD83. Blood 103: 4207-4215 [Abstract] [Full Text]  
• Huang, J., El-Gamil, M., Dudley, M. E., Li, Y. F., Rosenberg, S. A., Robbins, P. F. (2004). T Cells Associated with Tumor Regression Recognize Frameshifted Products of the CDKN2A Tumor Suppressor Gene Locus and a Mutated HLA Class I Gene Product. J. Immunol. 172: 6057-6064 [Abstract] [Full Text]  
• Li Pira, G., Bottone, L., Ivaldi, F., Pelizzoli, R., Del Galdo, F., Lozzi, L., Bracci, L., Loregian, A., Palu, G., De Palma, R., Einsele, H., Manca, F. (2004). Identification of new Th peptides from the cytomegalovirus protein pp65 to design a peptide library for generation of CD4 T cell lines for cellular immunoreconstitution. Int Immunol 16: 635-642 [Abstract] [Full Text]  
• Rauser, G., Einsele, H., Sinzger, C., Wernet, D., Kuntz, G., Assenmacher, M., Campbell, J. D. M., Topp, M. S. (2004). Rapid generation of combined CMV-specific CD4+ and CD8+ T-cell lines for adoptive transfer into recipients of allogeneic stem cell transplants. Blood 103: 3565-3572 [Abstract] [Full Text]  
• Verra, N. C. V., Jorritsma, A., Weijer, K., Ruizendaal, J. J., Voordouw, A., Weder, P., Hooijberg, E., Schumacher, T. N. M., Haanen, J. B. A. G., Spits, H., Luiten, R. M. (2004). Human Telomerase Reverse Transcriptase-Transduced Human Cytotoxic T Cells Suppress the Growth of Human Melanoma in Immunodeficient Mice. Cancer Res. 64: 2153-2161 [Abstract] [Full Text]  
• Boeckh, M., Nichols, W. G. (2004). The impact of cytomegalovirus serostatus of donor and recipient before hematopoietic stem cell transplantation in the era of antiviral prophylaxis and preemptive therapy. Blood 103: 2003-2008 [Abstract] [Full Text]  
• Atanackovic, D., Altorki, N. K., Stockert, E., Williamson, B., Jungbluth, A. A., Ritter, E., Santiago, D., Ferrara, C. A., Matsuo, M., Selvakumar, A., Dupont, B., Chen, Y.-T., Hoffman, E. W., Ritter, G., Old, L. J., Gnjatic, S. (2004). Vaccine-Induced CD4+ T Cell Responses to MAGE-3 Protein in Lung Cancer Patients. J. Immunol. 172: 3289-3296 [Abstract] [Full Text]  
• Stebbing, J., Gazzard, B., Patterson, S., Bower, M., Perumal, D., Nelson, M., McMichael, A., Ogg, G., Epenetos, A., Gotch, F., Savage, P. (2004). Antibody-targeted MHC complex-directed expansion of HIV-1- and KSHV-specific CD8+ lymphocytes: a new approach to therapeutic vaccination. Blood 103: 1791-1795 [Abstract] [Full Text]  
• Gibson, L., Piccinini, G., Lilleri, D., Revello, M. G., Wang, Z., Markel, S., Diamond, D. J., Luzuriaga, K. (2004). Human Cytomegalovirus Proteins pp65 and Immediate Early Protein 1 Are Common Targets for CD8+ T Cell Responses in Children with Congenital or Postnatal Human Cytomegalovirus Infection. J. Immunol. 172: 2256-2264 [Abstract] [Full Text]  
• Berger, C., Blau, C. A., Huang, M.-L., Iuliucci, J. D., Dalgarno, D. C., Gaschet, J., Heimfeld, S., Clackson, T., Riddell, S. R. (2004). Pharmacologically regulated Fas-mediated death of adoptively transferred T cells in a nonhuman primate model. Blood 103: 1261-1269 [Abstract] [Full Text]  
• Kondo, E., Akatsuka, Y., Kuzushima, K., Tsujimura, K., Asakura, S., Tajima, K., Kagami, Y., Kodera, Y., Tanimoto, M., Morishima, Y., Takahashi, T. (2004). Identification of novel CTL epitopes of CMV-pp65 presented by a variety of HLA alleles. Blood 103: 630-638 [Abstract] [Full Text]  
• Yue, Y., Zhou, S. S., Barry, P. A. (2003). Antibody responses to rhesus cytomegalovirus glycoprotein B in naturally infected rhesus macaques. J. Gen. Virol. 84: 3371-3379 [Abstract] [Full Text]  
• Roback, J. D., Hossain, M. S., Lezhava, L., Gorechlad, J. W., Alexander, S. A., Jaye, D. L., Mittelstaedt, S., Talib, S., Hearst, J. E., Hillyer, C. D., Waller, E. K. (2003). Allogeneic T Cells Treated with Amotosalen Prevent Lethal Cytomegalovirus Disease without Producing Graft-versus-Host Disease Following Bone Marrow Transplantation. J. Immunol. 171: 6023-6031 [Abstract] [Full Text]  
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• Gandhi, M. K., Wills, M. R., Okecha, G., Day, E. K., Hicks, R., Marcus, R. E., Sissons, J. G. P., Carmichael, A. J. (2003). Late diversification in the clonal composition of human cytomegalovirus-specific CD8+ T cells following allogeneic hemopoietic stem cell transplantation. Blood 102: 3427-3438 [Abstract] [Full Text]  
• Meijer, E., Boland, G. J., Verdonck, L. F. (2003). Prevention of Cytomegalovirus Disease in Recipients of Allogeneic Stem Cell Transplants. Clin. Microbiol. Rev. 16: 647-657 [Abstract] [Full Text]