Medicine and Health Sciences Commons^™

Cytokine Gene Expression Profiles During Initiation, Progression And Resolution Of Periodontitis, Jeffrey L. Ebersole, Sreenatha S. Kirakodu, Michael John Novak, Arnold J. Stromberg, Shu Shen, Luis Orraca, Janis Gonzalez-Martinez, Armando Burgos, Octavio A. Gonzalez

Center for Oral Health Research Faculty Publications

AIM: Variations in the expression of cytokines during the progression of periodontitis remain ill-defined. We evaluated the expression of 19 cytokine genes related to T-cell phenotype/function during initiation, progression and resolution of periodontitis, and related these to the expression of soft and bone tissue destruction genes (TDGs).

MATERIALS AND METHODS: A ligature-induced periodontitis model was used in rhesus monkeys (M. mulatta) (n = 18). Gingival tissues were taken at baseline pre-ligation, 2 weeks and 1 month (Initiation) and 3 months (progression) post ligation. Ligatures were removed and samples taken 2 months later (resolution). Total RNA was isolated and the Rhesus …

Viral Replication And Paracrine Effects Result In Distinct, Functional Responses Of Dendritic Cells Following Infection With Dengue 2 Virus, Zachary Nightingale, Chinmay Patkar, Alan Rothman

Alan Rothman

Dengue virus (DENV), a re-emerging arbovirus, readily infects dendritic cells (DC) in culture and in vivo. However, there have been contradictory reports regarding the effect of DENV infection on DC activation and maturation. DC undergo a series of functional changes following exposure to infectious agents, including cytokine production and costimulatory and MHC molecule induction, culminating in stimulation of adaptive immune responses. Immunological memory to primary DENV infection critically influences disease severity during subsequent infections with heterologous serotypes. To explore these phenomena, we examined DENV infection-dependent and -independent effects on DC secretory, phenotypic, and allostimulatory functions. DENV infection of DC resulted …

Impaired T Cell Proliferation In Acute Dengue Infection, Anuja Mathew, Ichiro Kurane, Sharone Green, David Vaughn, Siripen Kalayanarooj, Saroj Suntayakorn, Francis Ennis, Alan Rothman

Alan Rothman

Decreased proliferative responses to mitogens and recall Ags have been observed in PBMC obtained during several acute human viral infections. To determine whether cell-mediated responses are altered during acute dengue infection, we examined the proliferative responses of PBMC from children enrolled in a prospective study of dengue infections in Thailand. All responses of PBMC during acute illness were compared with the same patients' PBMC obtained at least 6 mo after their infection. Proliferative responses to PHA, anti-CD3, tetanus toxoid, and dengue Ags were decreased significantly in PBMC obtained during the acute infection. The proliferative responses to PHA were restored by …

Intracellular Cytokine Production By Dengue Virus-Specific T Cells Correlates With Subclinical Secondary Infection, Steven Hatch, Timothy Endy, Stephen Thomas, Anuja Mathew, James Potts, Pamela Pazoles, Daniel Libraty, Robert Gibbons, Alan Rothman

Alan Rothman

The pathophysiology of dengue virus infection remains poorly understood, although secondary infection is strongly associated with more severe disease. In the present study, we performed a nested, case-control study comparing the responses of pre-illness peripheral blood mononuclear cells between children who would subsequently develop either subclinical or symptomatic secondary infection 6-11 months after the baseline blood samples were obtained and frozen. We analyzed intracellular cytokine production by CD4(+) and CD8(+) cells in response to stimulation with dengue antigen. We found higher frequencies of dengue virus-specific TNFalpha, IFNgamma-, and IL-2-producing T cells among schoolchildren who subsequently developed subclinical infection, compared with …

T Cell Responses To An Hla-B*07-Restricted Epitope On The Dengue Ns3 Protein Correlate With Disease Severity, Iva Zivna, Sharone Green, David Vaughn, Siripen Kalayanarooj, Henry Stephens, Dasnayanee Chandanayingyong, Ananda Nisalak, Francis Ennis, Alan Rothman

Alan Rothman

Dengue hemorrhagic fever (DHF), the severe manifestation of dengue virus (DV) infection characterized by plasma leakage, is more common in secondary DV infections in previously infected individuals and is associated with high levels of immune activation. To determine the Ag specificity of this immune response, we studied the response to an HLA-B*07-restricted T cell epitope, residues 221-232 of the DV NS3 protein, in 10 HLA-B*07(+) Thai children who were studied during and after acute DV infections. Peptide-specific T cells were detected in 9 of 10 subjects. The frequency of peptide-specific T cells was higher in subjects who had experienced DHF …

Cross-Subtype Antibody And Cellular Immune Responses Induced By A Polyvalent Dna Prime-Protein Boost Hiv-1 Vaccine In Healthy Human Volunteers, Shixia Wang, Jeffrey Kennedy, Kim West, David Montefiori, Scott Coley, John Lawrence, Siyuan Shen, Sharone Green, Alan Rothman, Francis Ennis, James Arthos, Ranajit Pal, Phillip Markham, Shan Lu

Alan Rothman

An optimally effective AIDS vaccine would likely require the induction of both neutralizing antibody and cell-mediated immune responses, which has proven difficult to obtain in previous clinical trials. Here we report on the induction of Human Immunodeficiency Virus Type-1 (HIV-1)-specific immune responses in healthy adult volunteers that received the multi-gene, polyvalent, DNA prime-protein boost HIV-1 vaccine formulation, DP6-001, in a Phase I clinical trial conducted in healthy adult volunteers of both genders. Robust cross-subtype HIV-1-specific T cell responses were detected in IFNgamma ELISPOT assays. Furthermore, we detected high titer serum antibody responses that recognized a wide range of primary HIV-1 …

Transient Decreases In Human T Cell Proliferative Responses Following Vaccinia Immunization, Anuja Mathew, Francis Ennis, Alan Rothman

Alan Rothman

To further study the immunosuppression associated with virus infections, we analyzed the proliferative responses of serial PBMC samples obtained following vaccinia virus immunization. In four of five volunteers, responses to PHA, anti-CD3, vaccinia virus, and recall antigens were markedly decreased at at least one time point between days 5 and 29 after vaccination. Responses to PHA were restored by the addition of IL-2 or irradiated autologous healthy PBMC in the two volunteers tested, suggesting that the proliferation defect is attributable to accessory cell dysfunction. In one donor, immobilized anti-CD3 failed to induce proliferation, but addition of immobilized anti-CD28 partially restored …

Dengue Virus-Specific Murine T-Lymphocyte Proliferation: Serotype Specificity And Response To Recombinant Viral Proteins, Alan L. Rothman, Ichiro Kurane, Yi-Ming Zhang, Ching-Juh Lai, Francis A. Ennis

Alan Rothman

Definition of the T-lymphocyte responses to dengue viruses should aid in the development of safe and effective vaccines and help to explain the pathophysiology of dengue hemorrhagic fever and dengue shock syndrome. In this study, we demonstrated that dengue virus-specific T lymphocytes were detected in spleen cells from dengue virus-immune mice using an in vitro proliferation assay. Following immunization with a single dose of infectious dengue virus, murine lymphocytes showed increased proliferation when incubated in the presence of viral antigens of the same serotype but not in the presence of control antigens. Depletion experiments with antibody and complement showed that …

Discordance Between Antibody And T Cell Responses In Recipients Of Trivalent Inactivated Influenza Vaccine, Mary Co, Laura Orphin, John Cruz, Pamela Pazoles, Alan Rothman, Francis Ennis, Masanori Terajima

Alan Rothman

Thirty adults were tested for humoral and cellular immune responses following immunization with the trivalent inactivated influenza vaccine. Modest but significant inverse correlations between the baseline and the fold changes in the number of IFNgamma-producing cells and the levels of neutralizing antibodies were observed. Specific increases in proliferative responses in the CD8 CD45RA+ population were noted after vaccination. Minimal correlations between neutralizing antibody titers and the number of IFNgamma-producing cells in terms of prevaccination levels or fold increases were observed. These results show specific increases in a CD8 T cell subset and discordant T and B responses induced by the …

Vcam-1/Α4Β1 Integrin Interaction Is Crucial For Prompt Recruitment Of Immune T Cells Into The Brain During The Early Stage Of Reactivation Of Chronic Infection With Toxoplasma Gondii To Prevent Toxoplasmic Encephalitis, Qila Sa, Eri Ochiai, Tomoko Sengoku, Melinda E. Wilson, Morgan Brogli, Stephen Crutcher, Sara A. Michie, Baohui Xu, Laura Payne, Xisheng Wang, Yasuhiro Suzuki

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Reactivation of chronic infection with Toxoplasma gondii can cause life-threatening toxoplasmic encephalitis in immunocompromised individuals. We examined the role of VCAM-1/α4β1 integrin interaction in T cell recruitment to prevent reactivation of the infection in the brain. SCID mice were infected and treated with sulfadiazine to establish a chronic infection. VCAM-1 and ICAM-1 were the endothelial adhesion molecules detected on cerebral vessels of the infected SCID and wild-type animals. Immune T cells from infected wild-type mice were treated with anti-α4 integrin or control antibodies and transferred into infected SCID or nude mice, and the animals received the same antibody every other …

Comparative Analysis Of Gingival Tissue Antigen Presentation Pathways In Ageing And Periodontitis, Octavio A. Gonzalez, Michael John Novak, Sreenatha S. Kirakodu, Luis Orraca, Kuey-Chu Chen, Arnold J. Stromberg, Janis Gonzalez-Martinez, Jeffrey L. Ebersole

Center for Oral Health Research Faculty Publications

AIM: Gingival tissues of periodontitis lesions contribute to local elevations in mediators, including both specific T cell and antibody immune responses to oral bacterial antigens. Thus, antigen processing and presentation activities must exist in these tissues to link antigen-presenting cells with adaptive immunity. We hypothesized that alterations in the transcriptome of antigen processing and presentation genes occur in ageing gingival tissues and that periodontitis enhances these differences reflecting tissues less capable of immune resistance to oral pathogens.

MATERIALS AND METHODS: Rhesus monkeys (n = 34) from 3 to 23 years of age were examined. A buccal gingival sample from healthy …

Targeting Fibroblast Activation Protein In Tumor Stroma With Chimeric Antigen Receptor T Cells Can Inhibit Tumor Growth And Augment Host Immunity Without Severe Toxicity., Liang-Chuan S. Wang, Albert Lo, John Scholler, Jing Sun, Rajrupa S. Majumdar, Veena Kapoor, Michael Antzis, Cody E. Cotner, Laura A. Johnson, Amy C. Durham, Charalambos C. Solomides, Md, Carl H. June, Ellen Puré, Steven M. Albelda

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The majority of chimeric antigen receptor (CAR) T-cell research has focused on attacking cancer cells. Here, we show that targeting the tumor-promoting, nontransformed stromal cells using CAR T cells may offer several advantages. We developed a retroviral CAR construct specific for the mouse fibroblast activation protein (FAP), comprising a single-chain Fv FAP [monoclonal antibody (mAb) 73.3] with the CD8α hinge and transmembrane regions, and the human CD3ζ and 4-1BB activation domains. The transduced muFAP-CAR mouse T cells secreted IFN-γ and killed FAP-expressing 3T3 target cells specifically. Adoptively transferred 73.3-FAP-CAR mouse T cells selectively reduced FAP(hi) stromal cells and inhibited the …

Impaired T Cell Proliferation In Acute Dengue Infection, Anuja Mathew, Ichiro Kurane, Sharone Green, David Vaughn, Siripen Kalayanarooj, Saroj Suntayakorn, Francis Ennis, Alan Rothman

Sharone Green

Decreased proliferative responses to mitogens and recall Ags have been observed in PBMC obtained during several acute human viral infections. To determine whether cell-mediated responses are altered during acute dengue infection, we examined the proliferative responses of PBMC from children enrolled in a prospective study of dengue infections in Thailand. All responses of PBMC during acute illness were compared with the same patients' PBMC obtained at least 6 mo after their infection. Proliferative responses to PHA, anti-CD3, tetanus toxoid, and dengue Ags were decreased significantly in PBMC obtained during the acute infection. The proliferative responses to PHA were restored by …

T Cell Responses To An Hla-B*07-Restricted Epitope On The Dengue Ns3 Protein Correlate With Disease Severity, Iva Zivna, Sharone Green, David Vaughn, Siripen Kalayanarooj, Henry Stephens, Dasnayanee Chandanayingyong, Ananda Nisalak, Francis Ennis, Alan Rothman

Sharone Green

Dengue hemorrhagic fever (DHF), the severe manifestation of dengue virus (DV) infection characterized by plasma leakage, is more common in secondary DV infections in previously infected individuals and is associated with high levels of immune activation. To determine the Ag specificity of this immune response, we studied the response to an HLA-B*07-restricted T cell epitope, residues 221-232 of the DV NS3 protein, in 10 HLA-B*07(+) Thai children who were studied during and after acute DV infections. Peptide-specific T cells were detected in 9 of 10 subjects. The frequency of peptide-specific T cells was higher in subjects who had experienced DHF …

Cross-Subtype Antibody And Cellular Immune Responses Induced By A Polyvalent Dna Prime-Protein Boost Hiv-1 Vaccine In Healthy Human Volunteers, Shixia Wang, Jeffrey Kennedy, Kim West, David Montefiori, Scott Coley, John Lawrence, Siyuan Shen, Sharone Green, Alan Rothman, Francis Ennis, James Arthos, Ranajit Pal, Phillip Markham, Shan Lu

Sharone Green

An optimally effective AIDS vaccine would likely require the induction of both neutralizing antibody and cell-mediated immune responses, which has proven difficult to obtain in previous clinical trials. Here we report on the induction of Human Immunodeficiency Virus Type-1 (HIV-1)-specific immune responses in healthy adult volunteers that received the multi-gene, polyvalent, DNA prime-protein boost HIV-1 vaccine formulation, DP6-001, in a Phase I clinical trial conducted in healthy adult volunteers of both genders. Robust cross-subtype HIV-1-specific T cell responses were detected in IFNgamma ELISPOT assays. Furthermore, we detected high titer serum antibody responses that recognized a wide range of primary HIV-1 …