Browsing by Subject "Lymph Nodes"

Now showing 1 - 7 of 7
  • No Thumbnail Available
    ItemOpen Access
    Costimulation blockade alters germinal center responses and prevents antibody-mediated rejection.
    (Am J Transplant, 2014-01) Kim, EJ; Kwun, J; Gibby, AC; Hong, JJ; Farris III, AB; Iwakoshi, NN; Villinger, F; Kirk, AD; Knechtle, SJ
    De novo donor-specific antibody (DSA) after organ transplantation promotes antibody-mediated rejection (AMR) and causes late graft loss. Previously, we demonstrated that depletion using anti-CD3 immunotoxin combined with tacrolimus and alefacept (AMR regimen) reliably induced early DSA production with AMR in a nonhuman primate kidney transplant model. Five animals were assigned as positive AMR controls, four received additional belatacept and four received additional anti-CD40 mAb (2C10R4). Notably, production of early de novo DSA was completely attenuated with additional belatacept or 2C10R4 treatment. In accordance with this, while positive controls experienced a decrease in peripheral IgM(+) B cells, bela- and 2C10R4-added groups maintained a predominant population of IgM(+) B cells, potentially indicating decreased isotype switching. Central memory T cells (CD4(+) CD28(+) CD95(+)) as well as PD-1(hi) CD4(+) T cells were decreased in both bela-added and 2C10R4-added groups. In analyzing germinal center (GC) reactions in situ, lymph nodes further revealed a reduction of B cell clonal expansion, GC-follicular helper T (Tfh) cells, and IL-21 production inside GCs with additional belatacept or 2C10R4 treatment. Here we provide evidence that belatacept and 2C10R4 selectively suppresses the humoral response via regulating Tfh cells and prevents AMR in this nonhuman primate model.
  • Thumbnail Image
    ItemOpen Access
    Dosimetric assessment of rigid setup error by CBCT for HN-IMRT.
    (Journal of applied clinical medical physics, 2010-05-28) Worthy, Danielle; Wu, Qiuwen
    Dose distributions in HN-IMRT are complex and may be sensitive to the treatment uncertainties. The goals of this study were to evaluate: 1) dose differences between plan and actual delivery and implications on margin requirement for HN-IMRT with rigid setup errors; 2) dose distribution complexity on setup error sensitivity; and 3) agreement between average dose and cumulative dose in fractionated radiotherapy. Rigid setup errors for HN-IMRT patients were measured using cone-beam CT (CBCT) for 30 patients and 896 fractions. These were applied to plans for 12HN patients who underwent simultaneous integrated boost (SIB) IMRT treatment. Dose distributions were recalculated at each fraction and summed into cumulative dose. Measured setup errors were scaled by factors of 2-4 to investigate margin adequacy. Two plans, direct machine parameter optimization (DMPO) and fluence only (FO), were available for each patient to represent plans of different complexity. Normalized dosimetric indices, conformity index (CI) and conformation number (CN) were used in the evaluation. It was found that current 5 mm margins are more than adequate to compensate for rigid setup errors, and that standard margin recipes overestimate margins for rigid setup error in SIB HN-IMRT because of differences in acceptance criteria used in margin evaluation. The CTV-to-PTV margins can be effectively reduced to 1.9 mm and 1.5 mm for CTV1 and CTV2. Plans of higher complexity and sharper dose gradients are more sensitive to setup error and require larger margins. The CI and CN are not recommended for cumulative dose evaluation because of inconsistent definition of target volumes used. For fractionated radiotherapy in HN-IMRT, the average fractional dose does not represent the true cumulative dose received by the patient through voxel-by-voxel summation, primarily due to the setup error characteristics, where the random component is larger than systematic and different target regions get underdosed at each fraction.
  • Thumbnail Image
    ItemOpen Access
    M-HIFU inhibits tumor growth, suppresses STAT3 activity and enhances tumor specific immunity in a transplant tumor model of prostate cancer.
    (PLoS One, 2012) Huang, Xiaoyi; Yuan, Fang; Liang, Meihua; Lo, Hui-Wen; Shinohara, Mari L; Robertson, Cary; Zhong, Pei
    OBJECTIVE: In this study, we explored the use of mechanical high intensity focused ultrasound (M-HIFU) as a neo-adjuvant therapy prior to surgical resection of the primary tumor. We also investigated the role of signal transducer and activator of transcription 3 (STAT3) in M-HIFU elicited anti-tumor immune response using a transplant tumor model of prostate cancer. METHODS: RM-9, a mouse prostate cancer cell line with constitutively activated STAT3, was inoculated subcutaneously in C57BL/6J mice. The tumor-bearing mice (with a maximum tumor diameter of 5∼6 mm) were treated by M-HIFU or sham exposure two days before surgical resection of the primary tumor. Following recovery, if no tumor recurrence was observed in 30 days, tumor rechallenge was performed. The growth of the rechallenged tumor, survival rate and anti-tumor immune response of the animal were evaluated. RESULTS: No tumor recurrence and distant metastasis were observed in both treatment groups employing M-HIFU + surgery and surgery alone. However, compared to surgery alone, M-HIFU combined with surgery were found to significantly inhibit the growth of rechallenged tumors, down-regulate intra-tumoral STAT3 activities, increase cytotoxic T cells in spleens and tumor draining lymph nodes (TDLNs), and improve the host survival. Furthermore, M-HIFU combined with surgery was found to significantly decrease the level of immunosuppression with concomitantly increased number and activities of dendritic cells, compared to surgery alone. CONCLUSION: Our results demonstrate that M-HIFU can inhibit STAT3 activities, and when combined synergistically with surgery, may provide a novel and promising strategy for the treatment of prostate cancers.
  • Thumbnail Image
    ItemOpen Access
    Melanoma-Derived Wnt5a Promotes Local Dendritic-Cell Expression of IDO and Immunotolerance: Opportunities for Pharmacologic Enhancement of Immunotherapy.
    (Cancer Immunol Res, 2015-09) Holtzhausen, Alisha; Zhao, Fei; Evans, Kathy S; Tsutsui, Masahito; Orabona, Ciriana; Tyler, Douglas S; Hanks, Brent A
    The β-catenin signaling pathway has been demonstrated to promote the development of a tolerogenic dendritic cell (DC) population capable of driving regulatory T-cell (Treg) differentiation. Further studies have implicated tolerogenic DCs in promoting carcinogenesis in preclinical models. The molecular mechanisms underlying the establishment of immune tolerance by this DC population are poorly understood, and the methods by which developing cancers can co-opt this pathway to subvert immune surveillance are currently unknown. This work demonstrates that melanoma-derived Wnt5a ligand upregulates the durable expression and activity of the indoleamine 2,3-dioxygenase-1 (IDO) enzyme by local DCs in a manner that depends upon the β-catenin signaling pathway. These data indicate that Wnt5a-conditioned DCs promote the differentiation of Tregs in an IDO-dependent manner, and that this process serves to suppress melanoma immune surveillance. We further show that the genetic silencing of the PORCN membrane-bound O-acyl transferase, which is necessary for melanoma Wnt ligand secretion, enhances antitumor T-cell immunity, and that the pharmacologic inhibition of this enzyme synergistically suppresses melanoma progression when combined with anti-CTLA-4 antibody therapy. Finally, our data suggest that β-catenin signaling activity, based on a target gene expression profile that includes IDO in human sentinel lymph node-derived DCs, is associated with melanoma disease burden and diminished progression-free survival. This work implicates the Wnt-β-catenin signaling pathway as a novel therapeutic target in the melanoma immune microenvironment and demonstrates the potential impact of manipulating DC function as a strategy for optimizing tumor immunotherapy.
  • Thumbnail Image
    ItemOpen Access
    SIV-induced terminally differentiated adaptive NK cells in lymph nodes associated with enhanced MHC-E restricted activity.
    (Nature communications, 2021-02-24) Huot, Nicolas; Rascle, Philippe; Petitdemange, Caroline; Contreras, Vanessa; Stürzel, Christina M; Baquero, Eduard; Harper, Justin L; Passaes, Caroline; Legendre, Rachel; Varet, Hugo; Madec, Yoann; Sauermann, Ulrike; Stahl-Hennig, Christiane; Nattermann, Jacob; Saez-Cirion, Asier; Le Grand, Roger; Keith Reeves, R; Paiardini, Mirko; Kirchhoff, Frank; Jacquelin, Beatrice; Müller-Trutwin, Michaela
    Natural killer (NK) cells play a critical understudied role during HIV infection in tissues. In a natural host of SIV, the African green monkey (AGM), NK cells mediate a strong control of SIVagm infection in secondary lymphoid tissues. We demonstrate that SIVagm infection induces the expansion of terminally differentiated NKG2alow NK cells in secondary lymphoid organs displaying an adaptive transcriptional profile and increased MHC-E-restricted cytotoxicity in response to SIV Env peptides while expressing little IFN-γ. Such NK cell differentiation was lacking in SIVmac-infected macaques. Adaptive NK cells displayed no increased NKG2C expression. This study reveals a previously unknown profile of NK cell adaptation to a viral infection, thus accelerating strategies toward NK-cell directed therapies and viral control in tissues.
  • Thumbnail Image
    ItemOpen Access
    Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients.
    (Nature, 2015-03-19) Mitchell, Duane A; Batich, Kristen A; Gunn, Michael D; Huang, Min-Nung; Sanchez-Perez, Luis; Nair, Smita K; Congdon, Kendra L; Reap, Elizabeth A; Archer, Gary E; Desjardins, Annick; Friedman, Allan H; Friedman, Henry S; Herndon, James E; Coan, April; McLendon, Roger E; Reardon, David A; Vredenburgh, James J; Bigner, Darell D; Sampson, John H
    After stimulation, dendritic cells (DCs) mature and migrate to draining lymph nodes to induce immune responses. As such, autologous DCs generated ex vivo have been pulsed with tumour antigens and injected back into patients as immunotherapy. While DC vaccines have shown limited promise in the treatment of patients with advanced cancers including glioblastoma, the factors dictating DC vaccine efficacy remain poorly understood. Here we show that pre-conditioning the vaccine site with a potent recall antigen such as tetanus/diphtheria (Td) toxoid can significantly improve the lymph node homing and efficacy of tumour-antigen-specific DCs. To assess the effect of vaccine site pre-conditioning in humans, we randomized patients with glioblastoma to pre-conditioning with either mature DCs or Td unilaterally before bilateral vaccination with DCs pulsed with Cytomegalovirus phosphoprotein 65 (pp65) RNA. We and other laboratories have shown that pp65 is expressed in more than 90% of glioblastoma specimens but not in surrounding normal brain, providing an unparalleled opportunity to subvert this viral protein as a tumour-specific target. Patients given Td had enhanced DC migration bilaterally and significantly improved survival. In mice, Td pre-conditioning also enhanced bilateral DC migration and suppressed tumour growth in a manner dependent on the chemokine CCL3. Our clinical studies and corroborating investigations in mice suggest that pre-conditioning with a potent recall antigen may represent a viable strategy to improve anti-tumour immunotherapy.
  • Thumbnail Image
    ItemOpen Access