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2. Local delivery of granulocyte macrophage colony-stimulating factor by retrovirally transduced antigen-specific T cells leads to severe, chronic experimental autoimmune encephalomyelitis in mice

Author

Marusic, Suzana, primary, Miyashiro, Joy S, additional, Douhan, John, additional, Konz, Richard F, additional, Xuan, DeJun, additional, Pelker, Jeffrey W, additional, Ling, Vincent, additional, Leonard, John P, additional, and Jacobs, Kenneth A, additional

Published
2002
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3. IL-21 Limits NK Cell Responses and Promotes Antigen-Specific T Cell Activation

Author

Kasaian, Marion T, primary, Whitters, Matthew J, additional, Carter, Laura L, additional, Lowe, Leslie D, additional, Jussif, Jason M, additional, Deng, Bijia, additional, Johnson, Kaley A, additional, Witek, JoAnn S, additional, Senices, Mayra, additional, Konz, Richard F, additional, Wurster, Andrea L, additional, Donaldson, Debra D, additional, Collins, Mary, additional, Young, Deborah A, additional, and Grusby, Michael J, additional

Published
2002
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4. IL-21 Limits NK Cell Responses and Promotes Antigen-Specific T Cell Activation A Mediator of the Transition from Innate to Adaptive Immunity

Author

Kasaian, Marion T, Whitters, Matthew J, Carter, Laura L, Lowe, Leslie D, Jussif, Jason M, Deng, Bijia, Johnson, Kaley A, Witek, JoAnn S, Senices, Mayra, Konz, Richard F, Wurster, Andrea L, Donaldson, Debra D, Collins, Mary, Young, Deborah A, and Grusby, Michael J

Abstract

IFNα/β, IL-12, and IL-15 regulate NK cell activation and expansion, but signals triggering resolution of the NK response upon induction of adaptive immunity remain to be defined. We now report that IL-21, a product of activated T cells, may serve this function. Mice lacking IL-21R (IL-21R−/−) had normal NK cell development but no detectable responses to IL-21. IL-21 enhanced cytotoxic activity and IFNγ production by activated murine NK cells but did not support their viability, thus limiting their duration of activation. Furthermore, IL-21 blocked IL-15-induced expansion of resting NK cells, thus preventing the initiation of further innate responses. In contrast, IL-21 enhanced the proliferation, IFNγ production, and cytotoxic function of CD8+ effector T cells in an allogeneic MLR. These observations suggest that IL-21 promotes the transition between innate and adaptive immunity.

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5. Fas Activation of the p38 Mitogen-Activated Protein Kinase Signalling Pathway Requires ICE/CED-3 Family Proteases

Author

Juo, Peter, Kuo, Calvin J., Reynolds, Susan E., Konz, Richard F., Raingeaud, Joël, Davis, Roger J., Biemann, Hans-Peter, and Blenis, John

Abstract

The Fas receptor mediates a signalling cascade resulting in programmed cell death (apoptosis) within hours of receptor cross-linking. In this study Fas activated the stress-responsive mitogen-activated protein kinases, p38 and JNK, within 2 h in Jurkat T lymphocytes but not the mitogen-responsive kinase ERK1 or pp70S6k. Fas activation of p38 correlated temporally with the onset of apoptosis, and transfection of constitutively active MKK3 (glu), an upstream regulator of p38, potentiated Fas-induced cell death, suggesting a potential involvement of the MKK3/p38 activation pathway in Fas-mediated apoptosis. Fas has been shown to require ICE (interleukin-1 beta-converting enzyme) family proteases to induce apoptosis from studies utilizing the cowpox ICE inhibitor protein CrmA, the synthetic tetrapeptide ICE inhibitor YVAD-CMK, and the tripeptide pan-ICE inhibitor Z-VAD-FMK. In this study, crmA antagonized, and YVAD-CMK and Z-VAD-FMK completely inhibited, Fas activation of p38 kinase activity, demonstrating that Fas-dependent activation of p38 requires ICE/CED-3 family members and conversely that the MKK3/p38 activation cascade represents a downstream target for the ICE/CED-3 family proteases. Intriguingly, p38 activation by sorbitol and etoposide was resistant to YVAD-CMK and Z-VAD-FMK, suggesting the existence of an additional mechanism(s) of p38 regulation. The ICE/CED-3 family-p38 regulatory relationship described in the current work indicates that in addition to the previously described destructive cleavage of substrates such as poly(ADP ribose) polymerase, lamins, and topoisomerase, the apoptotic cysteine proteases also function to regulate stress kinase signalling cascades.

Published
1997
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6. IL-21 activates both innate and adaptive immunity to generate potent antitumor responses that require perforin but are independent of IFN-gamma.

Author

Ma HL, Whitters MJ, Konz RF, Senices M, Young DA, Grusby MJ, Collins M, and Dunussi-Joannopoulos K

Subjects
Adjuvants, Immunologic, Animals, Antigens, Neoplasm immunology, Cancer Vaccines genetics, Cancer Vaccines immunology, Cancer Vaccines metabolism, Cell Division genetics, Cell Division immunology, Cytotoxicity, Immunologic genetics, Female, Growth Inhibitors genetics, Growth Inhibitors metabolism, Immunity, Active genetics, Immunity, Innate genetics, Interferon-gamma metabolism, Interleukin-10 physiology, Interleukin-12 physiology, Interleukin-21 Receptor alpha Subunit, Interleukin-4 physiology, Interleukins genetics, Interleukins metabolism, Melanoma, Experimental genetics, Melanoma, Experimental metabolism, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Mice, Nude, Mice, SCID, Perforin, Pore Forming Cytotoxic Proteins, Receptors, Interleukin deficiency, Receptors, Interleukin genetics, Receptors, Interleukin physiology, Receptors, Interleukin-21, Sarcoma, Experimental genetics, Sarcoma, Experimental immunology, Sarcoma, Experimental metabolism, Sarcoma, Experimental therapy, T-Lymphocytes, Cytotoxic immunology, Transduction, Genetic, Tumor Cells, Cultured, Cancer Vaccines administration & dosage, Growth Inhibitors physiology, Interferon-gamma physiology, Interleukins administration & dosage, Interleukins physiology, Melanoma, Experimental immunology, Melanoma, Experimental therapy, Membrane Glycoproteins physiology
Abstract

IL-21 is a key factor in the transition between innate and adaptive immune responses. We have used the cytokine gene therapy approach to study the antitumor responses mediated by IL-21 in the B16F1 melanoma and MethA fibrosarcoma tumor models in mice. Retrovirally transduced tumor cells secreting biologically functional IL-21 have growth patterns in vitro similar to that of control green fluorescent protein-transduced cells, but are completely rejected in vivo. We show that IL-21 activates NK and CD8(+) T cells in vivo, thus mediating complete rejection of poorly immunogenic tumors. Rejection of IL-21-secreting tumors requires the presence of cognate IL-21R and does not depend on CD4(+) T cell help. Interestingly, perforin, but not IFN-gamma or other major Th1 and Th2 cytokines (IL-12, IL-4, or IL-10), is required for the IL-21-mediated antitumor response. Moreover, IL-21 results in 50% protection and 70% cure of nonimmunogenic tumors when given before and after tumor challenge, respectively, in C57BL/6 mice. We conclude that IL-21 immunotherapy warrants clinical evaluation as a potential treatment for cancer.

Published
2003
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