Browsing by Author "Güler, Ülkü"

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Enhancing preventive and therapeutic cancer vaccine efficacy through biotherapeutic ligand-associated extracellular vesicles
(Elsevier Ltd, 2024-12) Kahraman, Tamer; Akpınar, Gözde Güçlüler; Yıldırım, Muzaffer; Larssen, Pia; Bayyurt-Kocabaş, Banu; Yağcı, Fuat Cem; Gürsel, Arda; Horuluoğlu, Begüm Han; Yazar, Volkan; Ayanoğlu, İhsan Cihan; Yıldırım, Tuğce Canavar; Evcili, İrem; Yılmaz, İsmail Cem; Eldh, Maria; Gabrielsson, Susanne; Güler, Ülkü; Salih, Bekir; Gursel, Mayda; Gürsel, İhsan
Extracellular vesicles (EVs), secreted by almost all living cells, have gained significant attention for their role in intercellular communication and their potential as versatile carriers for biotherapeutics. However, the clinical translation of EV-based therapies faces significant challenges, primarily due to the lack of efficient methods for loading biotherapeutic agents into EVs. This study introduces a simple, reproducible strategy for the simultaneous incorporation of various biotherapeutics within EVs. The process is gentle and preserves the essential physicochemical and biological characteristics of EVs, thereby protecting labile ligands from premature degradation and elimination. The binding and uptake efficiency of EVs by target cells reached approximately 97 % within 24 h of incubation. Administration of EVs loaded with oligodeoxynucleotides (ODN) resulted in a 4-fold increase in $IFNy^{+}$ $CD4^{+}$ T cells and a 5-fold increase in $IFNy^{+}$ $CD8^{+}$ T cells in the spleens and lymph nodes. Additionally, the co-administration of EVs with ODN and ovalbumin (OVA) induced elevated Th1-biased antibody responses and antigen-specific cytotoxic T-cell responses, providing long-lasting complete protection in 60 % of mice against T-cell thymoma challenge. Furthermore, EVs associated with three different ligands (OVA, CpG-ODN, and α-GalCer) effectively regressed established murine melanoma and significantly improved survival rates in mice. This study presents a powerful and promising approach to overcoming the limitations of EV-based cancer vaccines, advancing the development of effective cancer immunotherapies.
Open Access
Human gut commensal membrane vesicles modulate inflammation by generating m2-like macrophages and myeloid-derived suppressor cells
(American Association of Immunologists, 2020) Bulut, E. A.; Kocabaş, Banu Bayyurt; Yazar, Volkan; Aykut, Gamze; Güler, Ülkü; Salih, B.; Yılmaz, N. S.; Ayanoglu, I. C.; Polat, M. M.; Akçalı, K. Ç.; Gürsel, İhsan; Gürsel, M.
Immunomodulatory commensal bacteria modify host immunity through delivery of regulatory microbial-derived products to host cells. Extracellular membrane vesicles (MVs) secreted from symbiont commensals represent one such transport mechanism. How MVs exert their anti-inflammatory effects or whether their tolerance-inducing potential can be used for therapeutic purposes remains poorly defined. In this study, we show that MVs isolated from the human lactic acid commensal bacteria Pediococcus pentosaceus suppressed Ag-specific humoral and cellular responses. MV treatment of bone marrow-derived macrophages and bone marrow progenitors promoted M2-like macrophage polarization and myeloid-derived suppressor cell differentiation, respectively, most likely in a TLR2-dependent manner. Consistent with their immunomodulatory activity, MV-differentiated cells upregulated expression of IL-10, arginase-1, and PD-L1 and suppressed the proliferation of activated T cells. MVs- antiinflammatory effects were further tested in acute inflammation models in mice. In carbon tetrachloride-induced fibrosis and zymosan-induced peritonitis models, MVs ameliorated inflammation. In the dextran sodium sulfate-induced acute colitis model, systemic treatment with MVs prevented colon shortening and loss of crypt architecture. In an excisional wound healing model, i.p. MV administration accelerated wound closure through recruitment of PD-L1-expressing myeloid cells to the wound site. Collectively, these results indicate that P. pentosaceus-derived MVs hold promise as therapeutic agents in management/treatment of inflammatory conditions.
Open Access
Immunogenicity and protective capacity of a CpG ODN adjuvanted alum adsorbed bivalent meningococcal outer membrane vesicle vaccine
(Oxford University Press, 2024-03-27) Yıldırım, Tuğçe Canavar; Özsürekçi, Yasemin; Yıldırım, Muzaffer; Evcili, İrem; Yazar, Volkan; Aykaç, Kübra; Güler, Ülkü; Salih, Bekir; Gürsel, Mayda; Gürsel, İhsan
Invasive meningococcal disease (IMD) is caused by Neisseria meningitidis, with the main serogroups responsible for the disease being A, B, C, W, X, and Y. To date, several vaccines targeting N. meningitidis have been developed albeit with a short-lived protection. Given that MenW and MenB are the most common causes of IMD in Europe, Turkey, and the Middle East, we aimed to develop an outer membrane vesicle (OMV) based bivalent vaccine as the heterologous antigen source. Herein, we compared the immunogenicity, and breadth of serum bactericidal activity (SBA) assay-based protective coverage of OMV vaccine to the X serotype with existing commercial meningococcal conjugate and polysaccharide (PS) vaccines in a murine model. BALB/c mice were immunized with preclinical batches of the W + B OMV vaccine, either adjuvanted with Alum, CpG ODN, or their combinations, and compared with a MenACYW conjugate vaccine (Nimenrix^TM, Pfizer), and a MenB OMV-based vaccine (Bexsero®, GSK), The immune responses were assessed through enzyme-linked immunosorbent assay (ELISA) and SBA assay. Antibody responses and SBA titers were significantly higher in the W + B OMV vaccine when adjuvanted with Alum or CpG ODN, as compared to the control groups. Moreover, the SBA titers were not only significantly higher than those achieved with available conjugated ACYW vaccines but also on par with the 4CMenB vaccines. In conclusion, the W + B OMV vaccine demonstrated the capacity to elicit robust antibody responses, surpassing or matching the levels induced by licensed meningococcal vaccines. Consequently, the W + B OMV vaccine could potentially serve as a viable alternative or supplement to existing meningococcal vaccines.
Open Access
Leishmania extracellular vesicles mediate protection against cutaneous leishmaniasis
(Wiley, 2024-09) Tokmak, İbrahim; Yılmaz, İsmail Cem; Giirse, Muzaffer Mayda; Yazar, Volkan; Salih, Bekir; Güler, Ülkü; Gürsel, İhsan; Gürsel, Mayda