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9. Multivalent 4-1BB binding aptamers costimulate [CD8.sup.+] T cells and inhibit tumor growth in mice

Author

McNamara, James O., II, Kolonias, Despina, Pastor, Fernando, Mittler, Robert S., Chen, Lieping, Giangrande, Paloma H., Sullenger, Bruce, and Gilboa, Eli

Subjects
Tumors -- Prevention, Tumors -- Research, Antigen presenting cells -- Research, Antigen presenting cells -- Physiological aspects, T cells -- Research, T cells -- Physiological aspects
Abstract

4-1BB is a major costimulatory receptor that promotes the survival and expansion of activated T cells. Administration of agonistic anti-4-1BB Abs has been previously shown to enhance tumor immunity in mice. Abs are cell-based products posing significant cost, manufacturing, and regulatory challenges. Aptamers are oligonucleotide-based ligands that exhibit specificity and avidity comparable to, or exceeding, that of Abs. To date, various aptamers have been shown to inhibit the function of their cognate target. Here, we have described the development of an aptamer that binds 4-1BB expressed on the surface of activated mouse T cells and shown that multivalent configurations of the aptamer costimulated T cell activation in vitro and mediated tumor rejection in mice. Because aptamers can be chemically synthesized, manufacturing and the regulatory approval process should be substantially simpler and less costly than for Abs. Agonistic aptamers could therefore represent a superior alternative to Abs for the therapeutic manipulation of the immune system., Introduction In addition to antigen-dependent TCR signaling, multiple costimulatory pathways regulate the potency, duration, and type of the T cell response. Experimental manipulation of costimulatory pathways offers an attractive way [...]

Published
2008

10. Immune suppression or enhancement by CD137 T cell costimulation during acute viral infection is time dependent

Author

Zhang, Benyue, Maris, Charles H., Foell, Juergen, Whitmire, Jason, Niu, Liguo, Song, Jing, Kwon, Byoung S., Vella, Anthony T., Ahmed, Rafi, Jacob, Joshy, and Mittler, Robert S.

Subjects
Immunity -- Health aspects, Immunity -- Research, Tumor necrosis factor -- Genetic aspects, Tumor necrosis factor -- Health aspects, Tumor necrosis factor -- Research, Virus diseases -- Risk factors, Virus diseases -- Research
Abstract

CD137 is expressed on activated T cells and ligands to this costimulatory molecule have clinical potential for amplifying CD8 T cell immunity to tumors and viruses, while suppressing CD4 autoimmune [...]

Published
2007

11. Eradication of established tumors in mice by a combination antibody-based therapy

Author

Uno, Tomoyasu, Takeda, Kazuyoshi, Kojima, Yuko, Yoshizawa, Hirohisa, Akiba, Hisaya, Mittler, Robert S, Gejyo, Fumitake, Okumura, Ko, Yagita, Hideo, and Smyth, Mark J

Abstract

Author(s): Tomoyasu Uno [1, 2]; Kazuyoshi Takeda (corresponding author) [1, 3]; Yuko Kojima [4]; Hirohisa Yoshizawa [5]; Hisaya Akiba [1]; Robert S Mittler [6]; Fumitake Gejyo [2]; Ko Okumura [1]; [...]

Published
2006
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13. Soluble CD137 Ameliorates Acute Type 1 Diabetes by Inducing T Cell Anergy

Author

Itoh, Arata, primary, Ortiz, Lorenzo, additional, Kachapati, Kritika, additional, Wu, Yuehong, additional, Adams, David, additional, Bednar, Kyle, additional, Mukherjee, Shibabrata, additional, Chougnet, Claire, additional, Mittler, Robert S., additional, Chen, Yi-Guang, additional, Dolan, Laurence, additional, and Ridgway, William M., additional

Published
2019
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25. Suppressing the self in rheumatoid arthritis

Author

Mittler, Robert S

Abstract

Author(s): Robert S Mittler [1] Rheumatoid arthritis causes chronic inflammation of peripheral joints, cartilage destruction and bone erosion [1] in approximately 1% of the human population (Fig. 1a). Treatment of [...]

Published
2004
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27. Long-lived antigen-induced IgM plasma cells demonstrate somatic mutations and contribute to long-term protection

Author

Bohannon, Caitlin, primary, Powers, Ryan, additional, Satyabhama, Lakshmipriyadarshini, additional, Cui, Ang, additional, Tipton, Christopher, additional, Michaeli, Miri, additional, Skountzou, Ioanna, additional, Mittler, Robert S., additional, Kleinstein, Steven H., additional, Mehr, Ramit, additional, Lee, Frances Eun-Yun, additional, Sanz, Ignacio, additional, and Jacob, Joshy, additional

Published
2016
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28. Humoral and Cell-Mediated Immune Responses to Alternate Booster Schedules of Anthrax Vaccine Adsorbed in Humans

Author

Quinn, Conrad P., primary, Sabourin, Carol L., additional, Schiffer, Jarad M., additional, Niemuth, Nancy A., additional, Semenova, Vera A., additional, Li, Han, additional, Rudge, Thomas L., additional, Brys, April M., additional, Mittler, Robert S., additional, Ibegbu, Chris C., additional, Wrammert, Jens, additional, Ahmed, Rafi, additional, Parker, Scott D., additional, Babcock, Janiine, additional, Keitel, Wendy, additional, Poland, Gregory A., additional, Keyserling, Harry L., additional, El Sahly, Hana, additional, Jacobson, Robert M., additional, Marano, Nina, additional, Plikaytis, Brian D., additional, and Wright, Jennifer G., additional

Published
2016
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29. The B10 Idd9.3 locus mediates accumulation of functionally superior CD137pos T regulatory cells in the NOD Type 1 diabetes model

Author

Kachapati, Kritika, Adams, David E., Wu, Yuehong, Steward, Charles A., Rainbow, Daniel B., Wicker, Linda S., Mittler, Robert S., and Ridgway, William M.

Subjects
Aging, Transplantation Chimera, hemic and immune systems, chemical and pharmacologic phenomena, Mice, Transgenic, T-Lymphocytes, Regulatory, Article, Diabetes Mellitus, Experimental, Mice, Tumor Necrosis Factor Receptor Superfamily, Member 9, Diabetes Mellitus, Type 1, Genetic Loci, Mice, Inbred NOD, Animals, Protein Isoforms, Transplantation, Homologous, Genetic Predisposition to Disease, Bone Marrow Transplantation
Abstract

CD137 is a T cell costimulatory molecule encoded by the prime candidate gene (designated Tnfrsf9) in NOD.B10 Idd9.3 congenic mice protected from type 1 diabetes (T1D). NOD T cells show decreased CD137-mediated T cell signaling compared with NOD.B10 Idd9.3 T cells, but it has been unclear how this decreased CD137 T cell signaling could mediate susceptibility to T1D. We and others have shown that a subset of regulatory T cells (Tregs) constitutively expresses CD137 (whereas effector T cells do not, and only express CD137 briefly after activation). In this study, we show that the B10 Idd9.3 region intrinsically contributes to accumulation of CD137(+) Tregs with age. NOD.B10 Idd9.3 mice showed significantly increased percentages and numbers of CD137(+) peripheral Tregs compared with NOD mice. Moreover, Tregs expressing the B10 Idd9.3 region preferentially accumulated in mixed bone marrow chimeric mice reconstituted with allotypically marked NOD and NOD.B10 Idd9.3 bone marrow. We demonstrate a possible significance of increased numbers of CD137(+) Tregs by showing functional superiority of FACS-purified CD137(+) Tregs in vitro compared with CD137(-) Tregs in T cell-suppression assays. Increased functional suppression was also associated with increased production of the alternatively spliced CD137 isoform, soluble CD137, which has been shown to suppress T cell proliferation. We show for the first time, to our knowledge, that CD137(+) Tregs are the primary cellular source of soluble CD137. NOD.B10 Idd9.3 mice showed significantly increased serum soluble CD137 compared with NOD mice with age, consistent with their increased numbers of CD137(+) Tregs with age. These studies demonstrate the importance of CD137(+) Tregs in T1D and offer a new hypothesis for how the NOD Idd9.3 region could act to increase T1D susceptibility.

Published
2012

30. Self-Antigen Prevents CD8 T Cell Effector Differentiation by CD134 and CD137 Dual Costimulation1

Author

Bandyopadhyay, Suman, Long, Meixiao, Qui, Harry Z., Hagymasi, Adam T., Slaiby, Aaron M., Mihalyo, Marianne A., Aguila, Hector L., Mittler, Robert S., Vella, Anthony T., and Adler, Adam J.

Subjects
CD4-Positive T-Lymphocytes, Quantitative Trait Loci, Cell Differentiation, Mice, Transgenic, CD8-Positive T-Lymphocytes, Receptors, OX40, Autoantigens, Article, Interferon-gamma, Mice, Tumor Necrosis Factor Receptor Superfamily, Member 9, Immune Tolerance, Animals, Peptides
Abstract

We compared how CD4 vs CD8 cells attain the capacity to express the effector cytokine IFN-gamma under both immunogenic and tolerogenic conditions. Although the Ifng gene locus was epigenetically repressed in naive Ag-inexperienced CD4 cells, it had already undergone partial remodeling toward a transcriptionally competent configuration in naive CD8 cells. After TCR stimulation, CD8 cells fully remodeled the Ifng locus and gained the capacity to express high levels of IFN-gamma more rapidly than CD4 cells. Enforced dual costimulation through OX40 and 4-1BB redirected CD8 cells encountering soluble exogenous peptide to expand and differentiate into IFN-gamma and TNF-alpha double-producing effectors rather than becoming tolerant. Despite this and the stronger tendency of CD8 compared with CD4 cells to differentiate into IFN-gamma-expressing effectors, when parenchymal self-Ag was the source of tolerizing Ag, enforced dual costimulation selectively boosted expansion but did not push effector differentiation in CD8 cells while both expansion and effector differentiation were dramatically boosted in CD4 cells. Notably, enforced dual costimulation was able to push effector differentiation in CD8 cells encountering cognate parenchymal self-Ag when CD4 cells were simultaneously engaged. Thus, the ability of enforced OX40 plus 4-1BB dual costimulation to redirect CD8 cells to undergo effector differentiation was unexpectedly influenced by the source of tolerizing Ag and help was selectively required to facilitate CD8 cell effector differentiation when the tolerizing Ag derived from self.

Published
2008

31. Cytokine-Mediated Disruption of Lymphocyte Trafficking, Hemopoiesis, and Induction of Lymphopenia, Anemia, and Thrombocytopenia in Anti-CD137-Treated Mice1

Author

Niu, Liguo, Strahotin, Simona, Hewes, Becker, Zhang, Benyue, Zhang, Yuanyuan, Archer, David, Spencer, Trent, Dillehay, Dirck, Kwon, Byoung, Chen, Lieping, Vella, Anthony T., and Mittler, Robert S.

Subjects
Receptors, Antigen, T-Cell, Antibodies, Monoclonal, Anemia, Mice, Inbred Strains, Lymphocyte Activation, Hematologic Diseases, Thrombocytopenia, Article, Hematopoiesis, Mice, Tumor Necrosis Factor Receptor Superfamily, Member 9, Liver, Cell Movement, Lymphopenia, Animals, Cytokines, Female, Lymph Nodes, Lymphocytes, Lung, Spleen, Cell Proliferation
Abstract

CD137-mediated signals costimulate T cells and protect them from activation-induced apoptosis; they induce curative antitumor immunity and enhance antiviral immune responses in mice. In contrast, anti-CD137 agonistic mAbs can suppress T-dependent humoral immunity and reverse the course of established autoimmune disease. These results have provided a rationale for assessing the therapeutic potential of CD137 ligands in human clinical trials. In this study, we report that a single 200-mug injection of anti-CD137 given to otherwise naive BALB/c or C57BL/6 mice led to the development of a series of immunological anomalies. These included splenomegaly, lymphadenopathy, hepatomegaly, multifocal hepatitis, anemia, altered trafficking of B cells and CD8 T cells, loss of NK cells, and a 10-fold increase in bone marrow (BM) cells bearing the phenotype of hemopoietic stem cells. These events were dependent on CD8 T cells, TNF-alpha, IFN-gamma, and type I IFNs. BM cells up-regulated Fas, and there was a significant increase in the number of CD8+ T cells that correlated with a loss of CD19+ and Ab-secreting cells in the BM. TCR Valphabeta usage was random and polyclonal among liver-infiltrating CD8 T cells, and multifocal CD8+ T cell infiltrates were resolved upon termination of anti-CD137 treatment. Anti-CD137-treated mice developed lymphopenia, thrombocytopenia, and anemia, and had lowered levels of hemoglobin and increased numbers of reticulocytes.

Published
2007

32. A Three-Dose Intramuscular Injection Schedule of Anthrax Vaccine Adsorbed Generates Sustained Humoral and Cellular Immune Responses to Protective Antigen and Provides Long-Term Protection against Inhalation Anthrax in Rhesus Macaques

Author

Quinn, Conrad P., primary, Sabourin, Carol L., additional, Niemuth, Nancy A., additional, Li, Han, additional, Semenova, Vera A., additional, Rudge, Thomas L., additional, Mayfield, Heather J., additional, Schiffer, Jarad, additional, Mittler, Robert S., additional, Ibegbu, Chris C., additional, Wrammert, Jens, additional, Ahmed, Rafi, additional, Brys, April M., additional, Hunt, Robert E., additional, Levesque, Denyse, additional, Estep, James E., additional, Barnewall, Roy E., additional, Robinson, David M., additional, Plikaytis, Brian D., additional, and Marano, Nina, additional

Published
2012
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46. Modulating Protective and Pathogenic CD4+ Subsets via CD137 in Type 1 Diabetes.

Author

Irie, Junichiro, Wu, Yuehong, Kachapati, Kritika, Ridgway, William M., and Mittler, Robert S.

Subjects
DIABETES, PREVENTIVE medicine, CD antigens, CD4 antigen, T cells, LABORATORY mice
Abstract

CD137 (TNFRSF9) is an activation-inducible T-cell co-stimulatory molecule and a member of the tumor necrosis factor (TNF) receptor superfamily. Cd137 is also a candidate gene (in the Idd9.3 interval) for autoimmune diabetes in NOD mice. Here, we demonstrate that anti-CD137 treatment protects NOD mice from diabetes. Anti-CD137-treated mice are not protected from insulitis and still harbor pathogenic T-cells, as demonstrated by transfer studies. Transfer of CD4[sup +], but not CD8[sup +], cells from anti-CD137-treated pre-diabetic NOD mice into NOD-scid mice delayed diabetes onset. Anti-CD137 treatment significantly increased the number of CD4[sup +]CD25[sup +] cells, which demonstrated intracellular Foxp3 expression and in vitro suppressive activity. The CD4[sup +]CD25[sup +] cell subset from anti-CD137-treated mice transferred complete protection from diabetes, whereas the CD4[sup +]CD25[sup -] cell subset offered no significant protection. Anti-CD137 treatment of NOD-scid recipients of diabetic spleen cells, however, hastened the onset of disease, showing that the effect of anti-CD137 treatment depends on the balance of pathogenic and protective cells. These results support a critical role for CD137 acting in the early phase of autoimmune diabetes to enhance regulatory cell production. Disease-associated CD137 alleles are likely ineffectual at stimulating a regulatory T-cell population sufficient to prevent disease. Diabetes 56:186-196, 2007 [ABSTRACT FROM AUTHOR]

Published
2007
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47. Polyspecific Self-Reactive Antibodies in Individuals Infected with Human Immunodeficiency Virus Facilitate T Cell Deletion and Inhibit Costimulatory Accessory Cell Function.

Author

Zhi-qin Qang, Orlikowsky, Thorsten, Bapat, Abhijit S., Rayanade, Ravi J., Soo Young Yang, Hoffmann, Michael K., Horowitz, Harold W., Beom-Ik Hahn, Trejo, Valia, and Mittler, Robert S.

Subjects
HIV antibodies, IMMUNOGLOBULINS, T cells
Abstract

Describes the presence of self-reacting antibodies in HIV-positive persons. Action on destroying human T cells in tissue culture; Reactivity with lymphocytes; Details of how exogenous costimulatory stimuli can reverse the inhibition.

Published
1999
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48. Lineage-specific T-cell reconstitution following in vivo CD4+and CD8+lymphocyte depletion in nonhuman primates

Author

Engram, Jessica C., Cervasi, Barbara, Borghans, Jose A.M., Klatt, Nichole R., Gordon, Shari N., Chahroudi, Ann, Else, James G., Mittler, Robert S., Sodora, Donald L., de Boer, Rob J., Brenchley, Jason M., Silvestri, Guido, and Paiardini, Mirko

Abstract

Many features of T-cell homeostasis in primates are still unclear, thus limiting our understanding of AIDS pathogenesis, in which T-cell homeostasis is lost. Here, we performed experiments of in vivo CD4+or CD8+lymphocyte depletion in 2 nonhuman primate species, rhesus macaques (RMs) and sooty mangabeys (SMs). Whereas RMs develop AIDS after infection with simian immunodeficiency virus (SIV), SIV-infected SMs are typically AIDS-resistant. We found that, in both species, most CD4+or CD8+T cells in blood and lymph nodes were depleted after treatment with their respective antibodies. These CD4+and CD8+lymphocyte depletions were followed by a largely lineage-specific CD4+and CD8+T-cell proliferation, involving mainly memory T cells, which correlated with interleukin-7 plasma levels. Interestingly, SMs showed a faster repopulation of naive CD4+T cells than RMs. In addition, in both species CD8+T-cell repopulation was faster than that of CD4+T cells, with CD8+T cells reconstituting a normal pool within 60 days and CD4+T cells remaining below baseline levels up to day 180 after depletion. While this study revealed subtle differences in CD4+T-cell repopulation in an AIDS-sensitive versus an AIDS-resistant species, such differences may have particular relevance in the presence of active SIV repli cation, where CD4+T-cell destruction is chronic.

Published
2010
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49. The IKK‐neutralizing compound Bay11 kills supereffector CD8 T cells by altering caspase‐dependent activation‐induced cell death

Author

Lee, Seung‐Joo, Long, Meixiao, Adler, Adam J., Mittler, Robert S., and Vella, Anthony T.

Abstract

Antigen with dual costimulation through CD137 and CD134 induces powerful CD8 T cell responses. These effector T cells are endowed with an intrinsic survival program resulting in their accumulation in vivo, but the signaling components required for survival are unknown. We tested a cadre of pathway inhibitors and found one preclinical compound, Bay11‐7082 (Bay11), which prevented survival. Even the γccytokine family members IL‐2, ‐4, ‐7, and ‐15 could not block death, nor could pretreatment with IL‐7. We found that dual costimulation caused loading of phosphorylated IκBα (p‐IκBα) and high basal levels of NF‐κB activity in the effector CD8 T cells. Bay11 trumped both events by reducing the presence of p‐IκBα and ensuing NF‐κB activity. Not all pathways were impacted to this degree, however, as mitogen‐mediated ERK phosphorylation was evident during NF‐κB inhibition. Nonetheless, Bay11 blocked TCR‐stimulated cytokine synthesis by rapidly accentuating activation‐induced cell death through elicitation of a caspase‐independent pathway. Thus, in effector CD8 T cells, Bay11 forces a dominant caspase‐independent death signal that cannot be overcome by an intrinsic survival program nor by survival‐inducing cytokines. Therefore, Bay11 may be a useful tool to deliberately kill death‐resistant effector T cells for therapeutic benefit.

Published
2009
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50. Antigen-Specific CD4+T Cells Recognize Epitopes of Protective Antigen following Vaccination with an Anthrax Vaccine

Author

Laughlin, Elsa M., Miller, Joseph D., James, Eddie, Fillos, Dimitri, Ibegbu, Chris C., Mittler, Robert S., Akondy, Rama, Kwok, William, Ahmed, Rafi, and Nepom, Gerald

Abstract

Detection of antigen-specific CD4+T cells is facilitated by the use of fluorescently labeled soluble peptide-major histocompatibility complex (MHC) multimers which mirror the antigen specificity of T-cell receptor recognition. We have used soluble peptide-MHC class II tetramers containing peptides from the protective antigen (PA) of Bacillus anthracis to detect circulating T cells in peripheral blood of subjects vaccinated with an anthrax vaccine. PA-specific HLA class II-restricted T lymphocytes were isolated which displayed both TH1- and TH2-like characteristics, indicating heterogeneity of the lymphocyte lineage within the CD4+response. Presentation of antigen to these T-cell clones by HLA-matched antigen-presenting cells exposed to the intact PA protein confirmed that the identified epitopes are indeed naturally processed by the human immune system. Specific tetramer-derived T-cell profiling may be useful for monitoring helper CD4+T-cell responses to anthrax vaccination.

Published
2007

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