Safety assessment of immunomodulatory biologics: The promise and challenges of regulatory T-cell modulation

References

• Abrams, D., Lévy, Y., Losso, M. H., Babiker, A., Collins, G., Cooper, D. A., Darbyshire, J., Emery, S., Fox, L., Gordin, F., Lane, H. C., Lundgren, J. D., Mitsuyasu, R., Neaton, J. D., Phillips, A., Routy, J. P., Tambussi, G. and Wentworth, D.; INSIGHT-ESPRIT Study Group; SILCAAT Scientific Committee. 2009. Interleukin-2 therapy in patients with HIV infection. N. Engl. J. Med. 361:1548–1559.
   PubMed Web of Science ®Google Scholar
• Almeida, A. R., Legrand, N., Papiernik, M. and Freitas, A. A. 2002. Homeostasis of peripheral CD4+ T-cells: IL-2R α and IL-2 shape a population of regulatory cells that controls CD4+ T-cell numbers. J. Immunol. 169:4850–4860.
   PubMed Web of Science ®Google Scholar
• Aluvihare, V. R., Kallikourdis, M. and Betz, A. G. 2004. Regulatory T-cells mediate maternal tolerance to the fetus. Nat. Immunol. 5:266–271.
   PubMed Web of Science ®Google Scholar
• Asano, M., Toda, M., Sakaguchi, N. and Sakaguchi, S. 1996. Autoimmune disease as a consequence of developmental abnormality of a T-cell subpopulation. J. Exp. Med. 184:387–396.
   PubMed Web of Science ®Google Scholar
• Atkins, M. B., Lotze, M. T., Dutcher, J. P., Fisher, R. I., Weiss, G., Margolin, K., Abrams, J., Sznol, M., Parkinson, D., Hawkins, M., Paradise, C., Kunkel, L. and Rosenberg, S. A. 1999. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: Analysis of 270 patients treated between 1985 and 1993. J. Clin. Oncol. 17:2105–2116.
   PubMed Web of Science ®Google Scholar
• Bennett, C. L., Christie, J., Ramsdell, F., Brunkow, M. E., Ferguson, P. J., Whitesell, L., Kelly, T. E., Saulsbury, F. T., Chance, P. F. and Ochs, H. D. 2001. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat. Genet. 27:20–21.
   PubMed Web of Science ®Google Scholar
• Blair, P. J., Bultman, S. J., Haas, J. C., Rouse, B. T., Wilkinson, J. E. and Godfrey, V. L. 1994. CD4+CD8– T-cells are the effector cells in disease pathogenesis in the scurfy (sf) mouse. J. Immunol. 153:3764–3774.
   PubMed Web of Science ®Google Scholar
• Bluestone, J. A. and Abbas, A. K. 2003. Natural versus adaptive regulatory T-cells. Nat. Rev. Immunol. 3:253–257.
   PubMed Web of Science ®Google Scholar
• Boros, P. and Bromberg, J. S. 2009. Human FOXP3+ regulatory T-cells in transplantation. Am. J. Transplant. 9:1719–1724.
   PubMed Web of Science ®Google Scholar
• Brunkow, M. E., Jeffery, E. W., Hjerrild, K. A., Paeper, B., Clark, L. B., Yasayko, S. A., Wilkinson, J. E., Galas, D., Ziegler, S. F. and Ramsdell, F. 2001. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat. Genet. 27:68–73.
   PubMed Web of Science ®Google Scholar
• Bugelski, P. J., Volk, A., Walker, M. R., Krayer, J. H., Martin, P., andDescotes, J 2010. Critical review of preclinical approaches to evaluate the potential of immunosuppressive drugs to influence human neoplasia. Int. J. Toxicol 29(5):435–466.
   PubMedGoogle Scholar
• Burnet, F. M. 1970. The concept of immunological surveillance. Prog. Exp. Tumor. Res. 13:1–27.
   PubMed Web of Science ®Google Scholar
• Chatila, T. A., Blaeser, F., Ho, N., Lederman, H. M., Voulgaropoulos, C., Helms, C. and Bowcock, A. M. 2000. JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome. J. Clin. Invest. 106:R75–R81.
   PubMed Web of Science ®Google Scholar
• CHMP, E. 2007. Guideline on strategies to identify and mitigate risks for first-in-human clinical trials with investigational medicinal products (Doc. Ref.EMEA/CHMP/SWP/28367/07). pp.1–12.
   Google Scholar
• Dunn, G. P., Bruce, A. T., Ikeda, H., Old, L. J. and Schreiber, R. D. 2002. Cancer immunoeditting: From immunosurveillance to tumor escape. Nat. Immunol. 3:991–998.
   PubMed Web of Science ®Google Scholar
• Dunn, G. P., Old, L. J. and Schreiber, R. D. 2004. The immunobiology of cancer immunosurveillance and immunoediting. Immunity. 21:137–148.
   PubMed Web of Science ®Google Scholar
• Eastwood, D., FIndlay, L., Poole, S., Bird, C., Wadhwa, M., Moore, M., Burns, C., Thorpe, R., andStebbings, R 2010. Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4+ effector memory T-cells. Br. J. Pharmacol. 161:512–526.
   PubMed Web of Science ®Google Scholar
• Elpek, K. G., Lacelle, C., Singh, N. P., Yolcu, E. S. and Shirwan, H. 2007. CD4+CD25+ T-regulatory cells dominate multiple immune evasion mechanisms in early but not late phases of tumor development in a B-cell lymphoma model. J. Immunol. 178:6840–6848.
   PubMedGoogle Scholar
• Engels, E. A., Biggar, R. J., Hall, H. I., Cross, H., Crutchfield, A., Finch, J. L., Grigg, R., Hylton, T., Pawlish, K. S., McNeel, T. S. and Goedert, J. J. 2008. Cancer risk in people infected with human immunodeficiency virus in the United States. Int. J. Cancer. 123:187–194.
   PubMed Web of Science ®Google Scholar
• Euvrard, S., Kanitakis, J., Pouteil-Noble, C., Claudy, A. and Touraine, J. L. 1997. Skin cancers in organ transplant recipients. Ann. Transplant. 2:28–32.
   PubMedGoogle Scholar
• Fontenot, J. D. and Rudensky, A. Y. 2005. A well adapted regulatory contrivance: regulatory T-cell development and the forkhead family transcription factor Foxp3. Nat. Immunol. 6:331–337.
   PubMed Web of Science ®Google Scholar
• Fontenot, J. D., Gavin, M. A. and Rudensky, A. Y. 2003. Foxp3 programs the development and function of CD4+CD25+ regulatory T-cells. Nat. Immunol. 4:330–336.
   PubMed Web of Science ®Google Scholar
• Fort, M. M. and Narayanan, P. K. 2010. Manipulation of regulatory T-cell function by immunomodulators: A boon or a curse? Toxicol. Sci. 117:253–262.
   PubMed Web of Science ®Google Scholar
• Gillis, S. and Smith, K. A. 1977. Long term culture of tumour-specific cytotoxic T-cells. Nature. 268:154–156.
   PubMed Web of Science ®Google Scholar
• Godin-Ethier, J., Pelletier, S., Hanafi, L. A., Gannon, P. O., Forget, M. A., Routy, J. P., Boulassel, M. R., Krzemien, U., Tanguay, S., Lattouf, J. B., Arbour, N. and Lapointe, R. 2009. Human activated T-lymphocytes modulate IDO expression in tumors through Th1/Th2 balance. J. Immunol. 183:7752–7760.
   PubMedGoogle Scholar
• Gorelik, L. and Flavell, R. A. 2000. Abrogation of TGFβ signaling in T-cells leads to spontaneous T-cell differentiation and autoimmune disease. Immunity. 12:171–181.
   PubMed Web of Science ®Google Scholar
• Gribble, E. J., Sivakumar, P. V., Ponce, R. A. and Hughes, S. D. 2007. Toxicity as a result of immunostimulation by biologics. Expert. Opin. Drug. Metab. Toxicol. 3:209–234.
   PubMed Web of Science ®Google Scholar
• Hanto, D. W., Frizzera, G., Gajl-Peczalska, K. J. and Simmons, R. L. 1985. Epstein-Barr virus, immunodeficiency, and B-cell lymphoproliferation. Transplantation. 39:461–472.
   PubMed Web of Science ®Google Scholar
• Henney, C. S., Kuribayashi, K., Kern, D. E. and Gillis, S. 1981. Interleukin-2 augments natural killer cell activity. Nature. 291:335–338.
   PubMed Web of Science ®Google Scholar
• Higano, C. S., Schellhammer, P. F., Small, E. J., Burch, P. A., Nemunaitis, J., Yuh, L., Provost, N. and Frohlich, M. W. 2009. Integrated data from 2 randomized, double-blind, placebo-controlled, Phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer. 115:3670–3679.
   PubMed Web of Science ®Google Scholar
• Hirschhorn-Cymerman, D., Rizzuto, G. A., Merghoub, T., Cohen, A. D., Avogadri, F., Lesokhin, A. M., Weinberg, A. D., Wolchok, J. D. and Houghton, A. N. 2009. OX40 engagement and chemotherapy combination provides potent antitumor immunity with concomitant regulatory T-cell apoptosis. J. Exp. Med. 206:1103–1116.
   PubMed Web of Science ®Google Scholar
• Hoption Cann, S. A., van Netten, J. P. and van Netten, C. 2003. Dr William Coley and tumour regression: a place in history or in the future. Postgrad. Med. J. 79:672–680.
   PubMed Web of Science ®Google Scholar
• Horak, I., Löhler, J., Ma, A. and Smith, K. A. 1995. Interleukin-2 deficient mice: A new model to study autoimmunity and self-tolerance. Immunol. Rev. 148:35–44.
   PubMed Web of Science ®Google Scholar
• Hori, S., Nomura, T. and Sakaguchi, S. 2003. Control of regulatory T-cell development by the transcription factor Foxp3. Science. 299:1057–1061.
   PubMed Web of Science ®Google Scholar
• Huang, M., Wang, J., Lee, P., Sharma, S., Mao, J. T., Meissner, H., Uyemura, K., Modlin, R., Wollman, J. and Dubinett, S. M. 1995. Human non-small cell lung cancer cells express a type 2 cytokine pattern. Cancer Res. 55:3847–3853.
   PubMed Web of Science ®Google Scholar
• Ichihara, F., Kono, K., Takahashi, A., Kawaida, H., Sugai, H. and Fujii, H. 2003. Increased populations of regulatory T-cells in peripheral blood and tumor-infiltrating lymphocytes in patients with gastric and esophageal cancers. Clin. Cancer. Res. 9:4404–4408.
   PubMed Web of Science ®Google Scholar
• Imai, H., Saio, M., Nonaka, K., Suwa, T., Umemura, N., Ouyang, G. F., Nakagawa, J., Tomita, H., Osada, S., Sugiyama, Y., Adachi, Y. and Takami, T. 2007. Depletion of CD4+CD25+ regulatory T-cells enhances interleukin-2-induced anti-tumor immunity in a mouse model of colon adenocarcinoma. Cancer. Sci. 98:416–423.
   PubMed Web of Science ®Google Scholar
• Jeal, W. and Goa, K. L. 1997. Aldesleukin (recombinant -2): A review of its pharmacological properties, clinical efficacy and tolerability in patients with renal cell carcinoma. Bio. Drugs. 7:285–317.
   Google Scholar
• Jones, E. A., Pringle, J. H., Angel, C. A. and Rees, R. C. 2002. Th1/Th2 cytokine expression and its relationship with tumor growth in B-cell non-Hodgkin’s lymphoma (NHL). Leuk. Lymphoma. 43:1313–1321.
   PubMed Web of Science ®Google Scholar
• Kantoff, P. W., Schuetz, T. J., Blumenstein, B. A., Glode, L. M., Bilhartz, D. L., Wyand, M., Manson, K., Panicali, D. L., Laus, R., Schlom, J., Dahut, W. L., Arlen, P. M., Gulley, J. L. and Godfrey, W. R. 2010. Overall survival analysis of a Phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. J. Clin. Oncol. 28:1099–1105.
   PubMed Web of Science ®Google Scholar
• Kaufman, H. L. and Bines, S. D. 2010. OPTIM trial: A Phase III trial of an oncolytic herpes virus encoding GM-CSF for unresectable stage III or IV melanoma. Future. Oncol. 6:941–949.
   PubMed Web of Science ®Google Scholar
• Khattri, R., Cox, T., Yasayko, S. A. and Ramsdell, F. 2003. An essential role for Scurfin in CD4+CD25+ T-regulatory cells. Nat. Immunol. 4:337–342.
   PubMed Web of Science ®Google Scholar
• Kim, J. M., Rasmussen, J. P. and Rudensky, A. Y. 2007. Regulatory T-cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat. Immunol. 8:191–197.
   PubMed Web of Science ®Google Scholar
• Kim, J., Lahl, K., Hori, S., Loddenkemper, C., Chaudhry, A., deRoos, P., Rudensky, A. and Sparwasser, T. 2009. Cutting edge: depletion of Foxp3+ cells leads to induction of autoimmunity by specific ablation of regulatory T-cells in genetically targeted mice. J. Immunol. 183:7631–7634.
   PubMedGoogle Scholar
• Ko, K., Yamazaki, S., Nakamura, K., Nishioka, T., Hirota, K., Yamaguchi, T., Shimizu, J., Nomura, T., Chiba, T. and Sakaguchi, S. 2005. Treatment of advanced tumors with agonistic anti-GITR mAb and its effects on tumor-infiltrating Foxp3+CD25+CD4+ regulatory T-cells. J. Exp. Med. 202:885–891.
   PubMed Web of Science ®Google Scholar
• Krämer, S., Schimpl, A. and Hünig, T. 1995. Immunopathology of interleukin (IL) 2-deficient mice: Thymus dependence and suppression by thymus-dependent cells with an intact IL-2 gene. J. Exp. Med. 182:1769–1776.
   PubMed Web of Science ®Google Scholar
• Lahl, K., Loddenkemper, C., Drouin, C., Freyer, J., Arnason, J., Eberl, G., Hamann, A., Wagner, H., Huehn, J. and Sparwasser, T. 2007. Selective depletion of Foxp3+ regulatory T-cells induces a scurfy-like disease. J. Exp. Med. 204:57–63.
   PubMedGoogle Scholar
• Leber, A., Teles, A. and Zenclussen, A. C. 2010. Regulatory T-cells and their role in pregnancy. Am J Reprod Immunol 63:445–459.
   PubMed Web of Science ®Google Scholar
• Leung, D. Y. and Bloom, J. W. 2003. Update on glucocorticoid action and resistance. J. Allergy. Clin. Immunol. 111:3–22 quiz 23.
   PubMed Web of Science ®Google Scholar
• Li, B., Samanta, A., Song, X., Iacono, K. T., Brennan, P., Chatila, T. A., Roncador, G., Banham, A. H., Riley, J. L., Wang, Q., Shen, Y., Saouaf, S. J. and Greene, M. I. 2007. FOXP3 is a homo-oligomer and a component of a supramolecular regulatory complex disabled in the human XLAAD/IPEX autoimmune disease. Int. Immunol. 19:825–835.
   PubMedGoogle Scholar
• Liyanage, U. K., Moore, T. T., Joo, H. G., Tanaka, Y., Herrmann, V., Doherty, G., Drebin, J. A., Strasberg, S. M., Eberlein, T. J., Goedegebuure, P. S. and Linehan, D. C. 2002. Prevalence of regulatory T-cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J. Immunol. 169:2756–2761.
   PubMed Web of Science ®Google Scholar
• Lyon, M. F., Peters, J., Glenister, P. H., Ball, S. and Wright, E. 1990. The scurfy mouse mutant has previously unrecognized hematological abnormalities and resembles Wiskott-Aldrich syndrome. Proc. Natl. Acad. Sci. USA. 87:2433–2437.
   PubMed Web of Science ®Google Scholar
• Malek, T. R. 2008. The biology of interleukin-2. Annu. Rev. Immunol. 26:453–479.
   PubMed Web of Science ®Google Scholar
• Malek, T. R. and Bayer, A. L. 2004. Tolerance, not immunity, crucially depends on IL-2. Nat. Rev. Immunol. 4:665–674.
   PubMed Web of Science ®Google Scholar
• Mantovani, A., Allavena, P., Sica, A. and Balkwill, F. 2008. Cancer-related inflammation. Nature. 454:436–444.
   PubMed Web of Science ®Google Scholar
• Mellor, A. L. and Munn, D. H. 2000. Immunology at the maternal-fetal interface: lessons for T-cell tolerance and suppression. Annu. Rev. Immunol. 18:367–391.
   PubMed Web of Science ®Google Scholar
• Morgan, D. A., Ruscetti, F. W. and Gallo, R. 1976. Selective in vitro growth of T-lymphocytes from normal human bone marrows. Science. 193:1007–1008.
   PubMed Web of Science ®Google Scholar
• Munn, D. H. and Mellor, A. L. 2007. Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J. Clin. Invest. 117:1147–1154.
   PubMed Web of Science ®Google Scholar
• Nguyen, D. H., Hurtado-Ziola, N., Gagneux, P. and Varki, A. 2006. Loss of Siglec expression on T-lymphocytes during human evolution. Proc. Natl. Acad. Sci. USA. 103:7765–7770.
   PubMed Web of Science ®Google Scholar
• Novartis. 2011. Proleukin® (aldesleukin) package insert.
   Google Scholar
• Onizuka, S., Tawara, I., Shimizu, J., Sakaguchi, S., Fujita, T. and Nakayama, E. 1999. Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor α) monoclonal antibody. Cancer. Res. 59:3128–3133.
   PubMed Web of Science ®Google Scholar
• Oppenheim, J. J. 2007. IL-2: More than a T cell growth factor. J. Immunol. 179:1413–1414.
   PubMedGoogle Scholar
• Penn, I. 1994. The problem of cancer in organ transplant recipients: An overview. Transplant. Sci. 4:23–32.
   PubMedGoogle Scholar
• Penn, I. 2000. Post-transplant malignancy: The role of immunosuppression. Drug. Saf. 23:101–113.
   PubMed Web of Science ®Google Scholar
• Piscitelli, S. C., Bhat, N. and Pau, A. 2000. A risk-benefit assessment of interleukin-2 as an adjunct to antiviral therapy in HIV infection. Drug. Saf. 22:19–31.
   PubMedGoogle Scholar
• Powrie, F., Carlino, J., Leach, M. W., Mauze, S. and Coffman, R. L. 1996. A critical role for transforming growth factor-β but not interleukin-4 in the suppression of T-helper type 1-mediated colitis by CD45RB(low) CD4+ T cells. J. Exp. Med. 183:2669–2674.
   PubMed Web of Science ®Google Scholar
• Read, S., Malmström, V. and Powrie, F. 2000. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J. Exp. Med. 192:295–302.
   PubMed Web of Science ®Google Scholar
• Ruscetti, F. W., Morgan, D. A. and Gallo, R. C. 1977. Functional and morphologic characterization of human T cells continuously grown in vitro. J. Immunol. 119:131–138.
   PubMed Web of Science ®Google Scholar
• Sadlack, B., Merz, H., Schorle, H., Schimpl, A., Feller, A. C. and Horak, I. 1993. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell. 75:253–261.
   PubMed Web of Science ®Google Scholar
• Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. and Toda, M. 1995. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor α-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155:1151–1164.
   PubMed Web of Science ®Google Scholar
• Schorle, H., Holtschke, T., Hünig, T., Schimpl, A. and Horak, I. 1991. Development and function of T-cells in mice rendered interleukin-2 deficient by gene targeting. Nature. 352:621–624.
   PubMed Web of Science ®Google Scholar
• Shimizu, J., Yamazaki, S. and Sakaguchi, S. 1999. Induction of tumor immunity by removing CD25+CD4+ T-cells: A common basis between tumor immunity and autoimmunity. J. Immunol. 163:5211–5218.
   PubMed Web of Science ®Google Scholar
• Soto, P. C., Stein, L. L., Hurtado-Ziola, N., Hedrick, S. M. and Varki, A. 2010. Relative over-reactivity of human versus chimpanzee lymphocytes: Implications for the human diseases associated with immune activation. J. Immunol. 184:4185–4195.
   PubMedGoogle Scholar
• Steiger, J., Nickerson, P. W., Steurer, W., Moscovitch-Lopatin, M. and Strom, T. B. 1995. IL-2 knockout recipient mice reject islet cell allografts. J. Immunol. 155:489–498.
   PubMedGoogle Scholar
• Suntharalingam, G., Perry, M. R., Ward, S., Brett, S. J., Castello-Cortes, A., Brunner, M. D. and Panoskaltsis, N. 2006. Cytokine storm in a Phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N. Engl. J. Med. 355:1018–1028.
   PubMed Web of Science ®Google Scholar
• Sutmuller, R. P., van Duivenvoorde, L. M., van Elsas, A., Schumacher, T. N., Wildenberg, M. E., Allison, J. P., Toes, R. E., Offringa, R. and Melief, C. J. 2001. Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25+ regulatory T-cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses. J. Exp. Med. 194:823–832.
   PubMed Web of Science ®Google Scholar
• Suzuki, H., Kündig, T. M., Furlonger, C., Wakeham, A., Timms, E., Matsuyama, T., Schmits, R., Simard, J. J., Ohashi, P. S. and Griesser, H. 1995. Deregulated T-cell activation and autoimmunity in mice lacking interleukin-2 receptor β. Science. 268:1472–1476.
   PubMed Web of Science ®Google Scholar
• Taniguchi, T., Matsui, H., Fujita, T., Takaoka, C., Kashima, N., Yoshimoto, R. and Hamuro, J. 1983. Structure and expression of a cloned cDNA for human interleukin-2. Nature. 302:305–310.
   PubMed Web of Science ®Google Scholar
• Vignali, D. A., Collison, L. W. and Workman, C. J. 2008. How regulatory T cells work. Nat. Rev. Immunol. 8:523–532.
   PubMed Web of Science ®Google Scholar
• Wiemann, B. and Starnes, C. O. 1994. Coley’s toxins, tumor necrosis factor and cancer research: A historical perspective. Pharmacol. Ther. 64:529–564.
   PubMed Web of Science ®Google Scholar
• Wildin, R. S., Smyk-Pearson, S. and Filipovich, A. H. 2002. Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J. Med. Genet. 39:537–545.
   PubMed Web of Science ®Google Scholar
• Woo, E. Y., Chu, C. S., Goletz, T. J., Schlienger, K., Yeh, H., Coukos, G., Rubin, S. C., Kaiser, L. R. and June, C. H. 2001. Regulatory CD4(+)CD25(+) T-cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer. Res. 61:4766–4772.
   PubMed Web of Science ®Google Scholar
• Zou, W. 2006. Regulatory T-cells, tumour immunity, and immunotherapy. Nat. Rev. Immunol. 6:295–307.
   PubMed Web of Science ®Google Scholar
• Zubler, R. H., Lowenthal, J. W., Erard, F., Hashimoto, N., Devos, R. and MacDonald, H. R. 1984. Activated B-cells express receptors for, and proliferate in response to, pure interleukin 2. J. Exp. Med. 160:1170–1183.
   PubMed Web of Science ®Google Scholar