FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 340:1704-1714 June 3, 1999 Number 22 Next

	Full Text PDF Editorial by Schwartz, R. S. Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

ABSTRACT

Background Successful allogeneic bone marrow transplantation relies on global immunosuppression or elimination of T cells. In contrast, the induction of anergy can inactivate specific sets of alloreactive T cells in the donor marrow. Previous work has shown that anergy can be induced by blocking the interaction of the B7 molecule on the surface of antigen-presenting cells with the CD28 molecule on the surface of T cells, thus preventing key signaling events essential for the activation of T cells. To investigate the feasibility of this approach with respect to transplantation of histoincompatible bone marrow, we undertook a clinical trial of ex vivo induction of anergy in T cells present in donor marrow to recipient alloantigens.

Methods Outcomes in 12 transplant recipients were evaluated. The recipients' peripheral-blood lymphocytes were collected before myeloablation and served as alloantigen-presenting cells. To induce alloantigen-specific anergy, bone marrow from a donor mismatched with the recipient for one HLA haplotype was cocultured with irradiated cells from the recipient for 36 hours in the presence of CTLA-4–Ig, an agent that inhibits B7:CD28-mediated costimulation. After conventional myeloablation and immunoprophylaxis, the treated donor cells were transfused into the recipient.

Results After the induction of anergy, the frequency of T cells capable of recognizing alloantigens of the recipient in donor marrow was sharply reduced (P<0.001), whereas the responsiveness to alloantigens from persons unrelated to the recipient or the donor was unaffected (P=0.51). In the 11 patients who could be evaluated, the haploidentical bone marrow cells engrafted. Of these 11 patients, 3 had acute graft-versus-host disease (GVHD) confined to the gastrointestinal tract. No deaths were attributable to GVHD. Five of the 12 patients were alive and in remission 4.5 to 29 months after transplantation.

Conclusions Donor bone marrow treated ex vivo to induce anergy to alloantigens from the recipient can reconstitute hematopoiesis in vivo with a relatively low risk of GVHD.

Source Information

From the Departments of Pediatric Oncology (E.C.G., L.L.B.), Adult Oncology (V.A.B., L.M.N., J.G.G.), and Biostatistics (D.N.), Dana–Farber Cancer Institute; the Division of Hematology and Oncology, Children's Hospital (E.C.G.); the Division of Medical Oncology, Brigham and Women's Hospital (V.A.B., N.H., L.M.N., J.G.G.); and the Departments of Pediatrics (E.C.G.) and Medicine (V.A.B., D.N., N.H., L.M.N., J.G.G.), Harvard Medical School — all in Boston.

Address reprint requests to Dr. Guinan at the Dana–Farber Cancer Institute, 44 Binney St., Boston, MA 02115, or at eva_guinan{at}dfci.harvard.edu.

Full Text of this Article

Related Letters:

Transplantation of Anergic Histoincompatible Bone Marrow Cells
de Carvalho Bittencourt M., Tiberghien P., Saas P., Gallardo D., Grañena A., García-López J.
Extract | Full Text  
N Engl J Med 1999; 341:1081-1082, Sep 30, 1999. Correspondence

This article has been cited by other articles:

• Davies, J. K., Gribben, J. G., Brennan, L. L., Yuk, D., Nadler, L. M., Guinan, E. C. (2008). Outcome of alloanergized haploidentical bone marrow transplantation after ex vivo costimulatory blockade: results of 2 phase 1 studies. Blood 112: 2232-2241 [Abstract] [Full Text]  
• Perez-Garcia, A., De la Camara, R., Roman-Gomez, J., Jimenez-Velasco, A., Encuentra, M., Nieto, J. B., de la Rubia, J., Urbano-Ispizua, A., Brunet, S., Iriondo, A., Gonzalez, M., Serrano, D., Espigado, I., Solano, C., Ribera, J. M., Pujal, J. M., Hoyos, M., Gallardo, D., the GVHD/Immunotherapy Committee of the Spanish Gr, (2007). CTLA-4 polymorphisms and clinical outcome after allogeneic stem cell transplantation from HLA-identical sibling donors.. Blood 110: 461-467 [Abstract] [Full Text]  
• Wehler, T. C., Nonn, M., Brandt, B., Britten, C. M., Grone, M., Todorova, M., Link, I., Khan, S. A., Meyer, R. G., Huber, C., Hartwig, U. F., Herr, W. (2007). Targeting the activation-induced antigen CD137 can selectively deplete alloreactive T cells from antileukemic and antitumor donor T-cell lines. Blood 109: 365-373 [Abstract] [Full Text]  
• Amrolia, P. J., Muccioli-Casadei, G., Huls, H., Adams, S., Durett, A., Gee, A., Yvon, E., Weiss, H., Cobbold, M., Gaspar, H. B., Rooney, C., Kuehnle, I., Ghetie, V., Schindler, J., Krance, R., Heslop, H. E., Veys, P., Vitetta, E., Brenner, M. K. (2006). Adoptive immunotherapy with allodepleted donor T-cells improves immune reconstitution after haploidentical stem cell transplantation. Blood 108: 1797-1808 [Abstract] [Full Text]  
• Perruccio, K., Tosti, A., Burchielli, E., Topini, F., Ruggeri, L., Carotti, A., Capanni, M., Urbani, E., Mancusi, A., Aversa, F., Martelli, M. F., Romani, L., Velardi, A. (2005). Transferring functional immune responses to pathogens after haploidentical hematopoietic transplantation. Blood 106: 4397-4406 [Abstract] [Full Text]  
• Koenen, H. J. P. M., Fasse, E., Joosten, I. (2005). CD27/CFSE-Based Ex Vivo Selection of Highly Suppressive Alloantigen-Specific Human Regulatory T Cells. J. Immunol. 174: 7573-7583 [Abstract] [Full Text]  
• Spitzer, T. R. (2005). Haploidentical Stem Cell Transplantation: The Always Present but Overlooked Donor. ASH Education Book 2005: 390-395 [Abstract] [Full Text]  
• Riley, J. L., June, C. H. (2005). The CD28 family: a T-cell rheostat for therapeutic control of T-cell activation. Blood 105: 13-21 [Abstract] [Full Text]  
• Martins, S. L. R., St. John, L. S., Champlin, R. E., Wieder, E. D., McMannis, J., Molldrem, J. J., Komanduri, K. V. (2004). Functional assessment and specific depletion of alloreactive human T cells using flow cytometry. Blood 104: 3429-3436 [Abstract] [Full Text]  
• Ichinohe, T., Uchiyama, T., Shimazaki, C., Matsuo, K., Tamaki, S., Hino, M., Watanabe, A., Hamaguchi, M., Adachi, S., Gondo, H., Uoshima, N., Yoshihara, T., Hatanaka, K., Fujii, H., Kawa, K., Kawanishi, K., Oka, K., Kimura, H., Itoh, M., Inukai, T., Maruya, E., Saji, H., Kodera, Y., for the Japanese Collaborative Study Group for NIM, (2004). Feasibility of HLA-haploidentical hematopoietic stem cell transplantation between noninherited maternal antigen (NIMA)-mismatched family members linked with long-term fetomaternal microchimerism. Blood 104: 3821-3828 [Abstract] [Full Text]  
• Iwasaki, T. (2004). Recent Advances in the Treatment of Graft-Versus-Host Disease. Clin Med Res 2: 243-252 [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]  
• Mapara, M. Y., Sykes, M. (2004). Tolerance and Cancer: Mechanisms of Tumor Evasion and Strategies for Breaking Tolerance. JCO 22: 1136-1151 [Abstract] [Full Text]  
• Zheng, Y., Manzotti, C. N., Liu, M., Burke, F., Mead, K. I., Sansom, D. M. (2004). CD86 and CD80 Differentially Modulate the Suppressive Function of Human Regulatory T Cells. J. Immunol. 172: 2778-2784 [Abstract] [Full Text]  
• Chen, B. J., Cui, X., Sempowski, G. D., Liu, C., Chao, N. J. (2004). Transfer of allogeneic CD62L- memory T cells without graft-versus-host disease. Blood 103: 1534-1541 [Abstract] [Full Text]  
• Yvon, E. S., Vigouroux, S., Rousseau, R. F., Biagi, E., Amrolia, P., Dotti, G., Wagner, H.-J., Brenner, M. K. (2003). Overexpression of the Notch ligand, Jagged-1, induces alloantigen-specific human regulatory T cells. Blood 102: 3815-3821 [Abstract] [Full Text]  
• Vassalli, G., Fleury, S., Li, J., Goy, J.-J., Kappenberger, L., von Segesser, L. K. (2003). Gene transfer of cytoprotective and immunomodulatory molecules for prevention of cardiac allograft rejection. Eur. J. Cardiothorac. Surg. 24: 794-806 [Abstract] [Full Text]  
• Amrolia, P. J., Muccioli-Casadei, G., Yvon, E., Huls, H., Sili, U., Wieder, E. D., Bollard, C., Michalek, J., Ghetie, V., Heslop, H. E., Molldrem, J. J., Rooney, C. M., Schlinder, J., Vitetta, E., Brenner, M. K. (2003). Selective depletion of donor alloreactive T cells without loss of antiviral or antileukemic responses. Blood 102: 2292-2299 [Abstract] [Full Text]  
• Tzachanis, D., Appleman, L. J., van Puijenbroek, A. A. F. L., Berezovskaya, A., Nadler, L. M., Boussiotis, V. A. (2003). Differential Localization and Function of ADP-Ribosylation Factor-6 in Anergic Human T Cells: A Potential Marker for Their Identification. J. Immunol. 171: 1691-1696 [Abstract] [Full Text]  
• Vasu, C., Gorla, S. R., Prabhakar, B. S., Holterman, M. J. (2003). Targeted engagement of CTLA-4 prevents autoimmune thyroiditis. Int Immunol 15: 641-654 [Abstract] [Full Text]  
• Barrett, A. J., Rezvani, K., Solomon, S., Dickinson, A. M., Wang, X. N., Stark, G., Cullup, H., Jarvis, M., Middleton, P. G., Chao, N. (2003). New Developments in Allotransplant Immunology. ASH Education Book 2003: 350-371 [Abstract] [Full Text]  
• Elssner, A., Jaumann, F., Wolf, W-P., Schwaiblmair, M., Behr, J., Furst, H., Reichenspurner, H., Briegel, J., Niedermeyer, J., Vogelmeier, C. (2002). Bronchial epithelial cell B7-1 and B7-2 mRNA expression after lung transplantation: a role in allograft rejection?. Eur Respir J 20: 165-169 [Abstract] [Full Text]  
• Guimond, M., Balassy, A., Barrette, M., Brochu, S., Perreault, C., Roy, D. C. (2002). P-glycoprotein targeting: a unique strategy to selectively eliminate immunoreactive T cells. Blood 100: 375-382 [Abstract] [Full Text]  
• Chen, B. J., Cui, X., Liu, C., Chao, N. J. (2002). Prevention of graft-versus-host disease while preserving graft-versus-leukemia effect after selective depletion of host-reactive T cells by photodynamic cell purging process. Blood 99: 3083-3088 [Abstract] [Full Text]  
• Hartwig, U. F., Robbers, M., Wickenhauser, C., Huber, C. (2002). Murine acute graft-versus-host disease can be prevented by depletion of alloreactive T lymphocytes using activation-induced cell death. Blood 99: 3041-3049 [Abstract] [Full Text]  
• Erbe, D. V., Wang, S., Xing, Y., Tobin, J. F. (2002). Small Molecule Ligands Define a Binding Site on the Immune Regulatory Protein B7.1. J. Biol. Chem. 277: 7363-7368 [Abstract] [Full Text]  
• Tzachanis, D., Berezovskaya, A., Nadler, L. M., Boussiotis, V. A. (2002). Blockade of B7/CD28 in mixed lymphocyte reaction cultures results in the generation of alternatively activated macrophages, which suppress T-cell responses. Blood 99: 1465-1473 [Abstract] [Full Text]  
• Drobyski, W. R., Klein, J., Flomenberg, N., Pietryga, D., Vesole, D. H., Margolis, D. A., Keever-Taylor, C. A. (2002). Superior survival associated with transplantation of matched unrelated versus one-antigen-mismatched unrelated or highly human leukocyte antigen- disparate haploidentical family donor marrow grafts for the treatment of hematologic malignancies: establishing a treatment algorithm for recipients of alternative donor grafts. Blood 99: 806-814 [Abstract] [Full Text]  
• Walters, M. C., Nienhuis, A. W., Vichinsky, E. (2002). Novel Therapeutic Approaches in Sickle Cell Disease. ASH Education Book 2002: 10-34 [Abstract] [Full Text]  
• Ho, V. T., Soiffer, R. J. (2001). The history and future of T-cell depletion as graft-versus-host disease prophylaxis for allogeneic hematopoietic stem cell transplantation. Blood 98: 3192-3204 [Full Text]  
• Liu, J., Anderson, B. E., Robert, M. E., McNiff, J. M., Emerson, S. G., Shlomchik, W. D., Shlomchik, M. J. (2001). Selective T-cell subset ablation demonstrates a role for T1 and T2 cells in ongoing acute graft-versus-host disease: a model system for the reversal of disease. Blood 98: 3367-3375 [Abstract] [Full Text]  
• Luznik, L., Jalla, S., Engstrom, L. W., Iannone, R., Fuchs, E. J. (2001). Durable engraftment of major histocompatibility complex-incompatible cells after nonmyeloablative conditioning with fludarabine, low-dose total body irradiation, and posttransplantation cyclophosphamide. Blood 98: 3456-3464 [Abstract] [Full Text]  
• Matsue, H., Matsue, K., Kusuhara, M., Kumamoto, T., Okumura, K., Yagita, H., Takashima, A. (2001). Immunosuppressive properties of CD95L-transduced "killer" hybrids created by fusing donor- and recipient-derived dendritic cells. Blood 98: 3465-3472 [Abstract] [Full Text]  
• Tazzari, P.-L., Polito, L., Bolognesi, A., Pistillo, M.-P., Capanni, P., Palmisano, G. L., Lemoli, R. M., Curti, A., Biancone, L., Camussi, G., Conte, R., Ferrara, G. B., Stirpe, F. (2001). Immunotoxins Containing Recombinant Anti-CTLA-4 Single-Chain Fragment Variable Antibodies and Saporin: In Vitro Results and In Vivo Effects in an Acute Rejection Model. J. Immunol. 167: 4222-4229 [Abstract] [Full Text]  
• Bittencourt, M. d. C., Perruche, S., Contassot, E., Fresnay, S., Baron, M.-H., Angonin, R., Aubin, F., Herve, P., Tiberghien, P., Saas, P. (2001). Intravenous injection of apoptotic leukocytes enhances bone marrow engraftment across major histocompatibility barriers. Blood 98: 224-230 [Abstract] [Full Text]  
• Strand, V (2001). Monoclonal antibodies and other biologic therapies. Lupus 10: 216-221 [Abstract]  
• Kapsogeorgou, E. K., Moutsopoulos, H. M., Manoussakis, M. N. (2001). Functional Expression of a Costimulatory B7.2 (CD86) Protein on Human Salivary Gland Epithelial Cells that Interacts with the CD28 Receptor, but Has Reduced Binding to CTLA4. J. Immunol. 166: 3107-3113 [Abstract] [Full Text]  
• Weinberg, K., Blazar, B. R., Wagner, J. E., Agura, E., Hill, B. J., Smogorzewska, M., Koup, R. A., Betts, M. R., Collins, R. H., Douek, D. C. (2001). Factors affecting thymic function after allogeneic hematopoietic stem cell transplantation. Blood 97: 1458-1466 [Abstract] [Full Text]  
• Lu, Y., Sakamaki, S., Kuroda, H., Kusakabe, T., Konuma, Y., Akiyama, T., Fujimi, A., Takemoto, N., Nishiie, K., Matsunaga, T., Hirayama, Y., Kato, J., Kon, S., Kogawa, K., Niitsu, Y. (2001). Prevention of lethal acute graft-versus-host disease in mice by oral administration of T helper 1 inhibitor, TAK-603. Blood 97: 1123-1130 [Abstract] [Full Text]  
• Niklason, L. E., Langer, R. (2001). Prospects for Organ and Tissue Replacement. JAMA 285: 573-576 [Abstract] [Full Text]  
• Silberstein, L. E., Toy, P. (2001). Research Opportunities in Transfusion Medicine. JAMA 285: 577-580 [Abstract] [Full Text]  
• Lee, R. S., Rusche, J. R., Maloney, M. E., Sachs, D. H., Sayegh, M. H., Madsen, J. C. (2001). CTLA4Ig-Induced Linked Regulation of Allogeneic T Cell Responses. J. Immunol. 166: 1572-1582 [Abstract] [Full Text]  
• Boussiotis, V. A., Chen, Z.-M., Zeller, J. C., Murphy, W. J., Berezovskaya, A., Narula, S., Roncarolo, M. G., Blazar, B. R. (2001). Altered T-cell receptor + CD28-mediated signaling and blocked cell cycle progression in interleukin 10 and transforming growth factor-{beta}-treated alloreactive T cells that do not induce graft-versus-host disease. Blood 97: 565-571 [Abstract] [Full Text]  
• Godder, K. T., Hazlett, L. J., Abhyankar, S. H., Chiang, K. Y., Christiansen, N. P., Bridges, K. D., Lee, C. G., Geier, S. S., Goon-Johnson, K. S., Gee, A. P., Pati, A. R., Parrish, R. S., Henslee-Downey, P. J. (2000). Partially Mismatched Related-Donor Bone Marrow Transplantation for Pediatric Patients With Acute Leukemia: Younger Donors and Absence of Peripheral Blasts Improve Outcome. JCO 18: 1856-1866 [Abstract] [Full Text]  
• Lee, R. S., Yamada, K., Womer, K. L., Pillsbury, E. P., Allison, K. S., Marolewski, A. E., Geng, D., Thall, A. D., Arn, J. S., Sachs, D. H., Sayegh, M. H., Madsen, J. C. (2000). Blockade of CD28-B7, But Not CD40-CD154, Prevents Costimulation of Allogeneic Porcine and Xenogeneic Human Anti-Porcine T Cell Responses. J. Immunol. 164: 3434-3444 [Abstract] [Full Text]  
• Seung, E., Iwakoshi, N., Woda, B. A., Markees, T. G., Mordes, J. P., Rossini, A. A., Greiner, D. L. (2000). Allogeneic hematopoietic chimerism in mice treated with sublethal myeloablation and anti-CD154 antibody: absence of graft-versus-host disease, induction of skin allograft tolerance, and prevention of recurrent autoimmunity in islet-allografted NOD/Lt mice. Blood 95: 2175-2182 [Abstract] [Full Text]  
• Qian, J., Collins, M., Sharpe, A. H., Hoyer, L. W. (2000). Prevention and treatment of factor VIII inhibitors in murine hemophilia A. Blood 95: 1324-1329 [Abstract] [Full Text]  
• Lowdell, M. W, Koh, M. B C (2000). Immunotherapy of AML: future directions. J. Clin. Pathol. 53: 49-54 [Full Text]  
• Appleman, L. J., Berezovskaya, A., Grass, I., Boussiotis, V. A. (2000). CD28 Costimulation Mediates T Cell Expansion Via IL-2-Independent and IL-2-Dependent Regulation of Cell Cycle Progression. J. Immunol. 164: 144-151 [Abstract] [Full Text]  
• de Carvalho Bittencourt, M., Tiberghien, P., Saas, P., Gallardo, D., Granena, A., Garcia-Lopez, J. (1999). Transplantation of Anergic Histoincompatible Bone Marrow Cells. NEJM 341: 1081-1082 [Full Text]  
• Schwartz, R. S. (1999). The New Immunology -- The End of Immunosuppressive Drug Therapy?. NEJM 340: 1754-1756 [Full Text]