Ingo Fricke - Academia.edu (original) (raw)
Papers by Ingo Fricke
Since 2019, notable global viral outbreaks have occurred necessitating further research and healt... more Since 2019, notable global viral outbreaks have occurred necessitating further research and healthcare system investigations. Following the COVID—19 pandemic, an unexpected duality has occurred of SARS–CoV–2 and monkeypox virus (MPXV) infections. Monkeypox virus is of the Orthopoxviridae genus, belonging to the family Poxviridae. Zoonotic transmission (animal to human transmission) may occur. The Orthopoxviridae genus includes other Orthopoxviruses (OPXV) present in animal host reservoirs that include cowpox viruses (CPXV), vaccinia virus (VACV) and variola virus (VARV), with the latter being causal agent of smallpox and excessive mortality. The aim in this review is to present facts about MPXV specific pathogenesis, epidemiology, and immunology alongside historical perspectives. Monkeypox virus was rarely reported outside Africa before April 2000. Early research since 1796 contributed towards eradication of VARV leading to immunisation strategies. The World Health Organisation (WHO...
We have outlined the idea of creating a synthetic standardized convalescent plasma with assigned ... more We have outlined the idea of creating a synthetic standardized convalescent plasma with assigned neutralization capacity and a vaccine strategy using a multipeptide approach targeting the mucosal immune system.
Cancer Research, Apr 15, 2006
Proc Amer Assoc Cancer Res, Volume 47, 2006 4877 Abnormal differentiation of dendritic cells (DC)... more Proc Amer Assoc Cancer Res, Volume 47, 2006 4877 Abnormal differentiation of dendritic cells (DC) in cancer manifests in decreased presence and impaired function of mature DCs and the appearance of a larger number of immature myeloid cells (ImC) that are capable of suppressing antigen-specific T cells. Recently it becomes increasingly clear that success of immune intervention in cancer will depend on the ability to remove ImC and improve differentiation of DCs. Previous in vitro and in vivo studies in tumor-bearing mice suggested that all-trans-retinoic acid (ATRA) could improve DC differentiation and eliminate ImC. Here, we for the first time have tested the effect of ATRA on DCs and ImC in cancer patients. Eighteen patients with advanced stage renal cell carcinoma (RCC) were enrolled onto the study and received treatment with ATRA (50-150 mg/m2/day) for seven days. Seven days after completion of ATRA treatment patients started IL-2 therapy for five consecutive weeks. Peripheral blood was collected weekly. In parallel blood was collected from 16 patients that received IL-2 therapy alone. Control group comprised 7 healthy volunteers. Mononuclear cells (MNC) isolated at each time point were stored in liquid nitrogen. All samples from the same patient were analyzed simultaneously. After thawing MNC were cultured overnight and then were labeled with a cocktail of lineage specific antibodies (anti-CD3, CD19, CD56 and CD14), anti-HLA-DR antibody, anti-CD33 antibody, and either anti-CD86, anti-CD40, anti-CD83, or anti-CCR7 antibodies. ImC were defined as Lin negative, HLA-DR negative, CD33 positive cells. DCs were defined as lineage negative, HLA-DR positive cells. In addition, the presence of myeloid and plasmocytoid subsets of DCs was determined using anti-CD11c and anti-CD123 antibodies. Cells were evaluated by flow cytometry. The proportions of different populations of DCs were calculated. In addition the response of MNC to antigen (tetanus toxoid) and mitogen (PHA) was evaluated as well as the ability of DCs to stimulate allogeneic T cells. To date no adverse effect of the therapy was reported. This trial is at an early stage, however, the initial results are very encouraging. As expected almost all patients with metastatic RCC had increased level of ImC. ATRA treatment substantially decreased the number of ImC in more than 90% of them. In 60% of patients the presence of ImC was reduced to the control level. ATRA treatment substantially increased the proportion and functional activity of DCs. The presence of CD83+ or CD40+ mature DCs was also increased. These first results suggest that ATRA may substantially improve DC differentiation and eliminate ImC in cancer patients. It could be a valuable addition to different cancer immunotherapeutic strategies.
Nucleic Acids Research, 2002
CSDBase (http://www.chemie.uni-marburg.de/\~csdbase/) is an interactive Internet-embedded research... more CSDBase (http://www.chemie.uni-marburg.de/~csdbase/) is an interactive Internet-embedded research platform providing detailed information on proteins containing the cold shock domain (CSD). It consists of two separated database cores, one dedicated to CSD protein information, and one to provide a powerful resource to relevant literature with emphasis on the bacterial cold shock response. In addition to detailed protein information and useful cross links to other web sites, CSDBase contains computer-generated CSD structure models for most CSD-containing protein sequences available at NCBI non-redundant protein database at the time of CSDBase establishment. These models were calculated on the basis of known crystal and/or NMR structures using SWISS-MODEL and can be downloaded as PDB structure coordinate files for viewing and for manipulation with other software tools. CSDBase will be regularly updated and is organized in a compact form providing user friendly interfaces to both database cores which allow for easy data retrieval.
Clinical Cancer Research, Feb 1, 2006
The initial goal of this study was to test the immunologic and clinical effects of a new cancer v... more The initial goal of this study was to test the immunologic and clinical effects of a new cancer vaccine consisting of dendritic cells (DC) transduced with the full-length wild-type p53 gene delivered via an adenoviral vector in patients with extensive stage small cell lung cancer. Experimental Design: Twenty-nine patients with extensive stage small cell lung cancer were vaccinated repeatedly at 2-week intervals. Most of the patients received three immunizations. p53-specific responses were evaluated, and phenotype and function of Tcells, DCs, and immature myeloid cells were analyzed and correlated with antigen-specific immune responses. Objective clinical response to vaccination as well as subsequent chemotherapy was evaluated. Results: p53-specificTcell responses to vaccination were observed in 57.1% of patients. Immunologic responses to vaccination were positively associated with a moderate increase in the titer of antiadenovirus antibodies, and negatively with an accumulation of immature myeloid cells. One patient showed a clinical response to vaccination whereas most of the patients had disease progression. However, we observed a high rate of objective clinical responses to chemotherapy (61.9%) that immediately followed vaccination. Clinical response to subsequent chemotherapy was closely associated with induction of immunologic response to vaccination. Conclusions: This study provides clinical support for an emerging paradigm in cancer immunotherapy, wherein optimal use of vaccination might be more effective, not as a separate modality, but in direct combination with chemotherapy.
The coronavirus 2019 (COVID-19) pandemic was caused by a positive sense singlestranded RNA (ssRNA... more The coronavirus 2019 (COVID-19) pandemic was caused by a positive sense singlestranded RNA (ssRNA) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, other human coronaviruses (hCoVs) exist, of which Middle East Respiratory Syndrome (MERS) and SARS-CoV (SARS) showed higher mortality rates without causing a pandemic. As of December 2022, SARS-CoV-2 has resulted in over 6.6 million deaths worldwide through an array of acute to chronic pathologies. Historical pandemics include smallpox and influenza with efficacious therapeutics utilized to reduce overall disease burden. Therefore, immune system process analysis is required to compare innate and adaptive immune system interactions. Lymphatic system organs include bone marrow and thymus using a network of nodes throughout which white blood cells traverse glycolipid membranes utilizing cytokines and chemokine gradients that affect cell development, differentiation, proliferation, and migration processes as well as genetic factors affecting cell receptor expression.
Clinical Cancer Research, Aug 15, 2007
Induction of antitumor immune responses requires adequate function of dendritic cells. Dendritic ... more Induction of antitumor immune responses requires adequate function of dendritic cells. Dendritic cell defects in cancer patients have been implicated in tumor escape and the limited efficacy of cancer vaccines. Previous studies have shown that vascular endothelial growth factor (VEGF) plays a major role in abnormal dendritic cell differentiation and function in cancer. It has been proposed that inhibition of VEGF may result in improved immune responses. The goal of this study was to test this hypothesis. Experimental Design: Fifteen patients with refractory solid tumors were enrolled into a phase I clinical trial of VEGF-Trap. Phenotype and function of different subsets of mononuclear cells were measured before and at different time points after the start of treatment. Results: VEGF-Trap treatment did not affect the total population of dendritic cells, their myeloid or plasmacytoid subsets, myeloid-derived suppressor cells (MDSC), or regulatory T cells. It significantly increased the proportion of mature dendritic cells. However, that improvement was not associated with an overall increase in immune responses to various antigens and mitogens. A subset analysis revealed significant improvement in immune responses in patients who had no increase in the proportion of MDSC. An improvement in immune responses was absent in patients with an increase in the proportion of MDSC. Conclusions: Inhibition of VEGF signaling may improve differentiation of dendritic cells in cancer patients. However, it was not sufficient to improve immune responses. This shows multifaceted nature of immune deficiency and points out to the need for complex approach to modulation of immune reactivity in cancer.
Journal of Immunology, May 1, 2006
R753Q polymorphism compromises TLR2 signaling functions by altering TLR6-TLR2 hetero-dimerization... more R753Q polymorphism compromises TLR2 signaling functions by altering TLR6-TLR2 hetero-dimerization, TLR2 tyrosine phosphorylation and MyD88 recruitment (180.2)
Immunological Investigations, 2006
The fact that the immune response to cancer is compromised has been convincingly demonstrated in ... more The fact that the immune response to cancer is compromised has been convincingly demonstrated in murine tumor models as well as in cancer patients. The unresponsiveness of the host immune system is one of the major mechanisms of tumor escape as well as an important factor that limits the success of cancer immunotherapy. Inadequate function of professional antigen presenting cells dendritic cells (DC) in cancer is one of the major elements of compromised anti-tumor immune response. Despite substantial progress in recent years, the mechanism of inadequate DC function in cancer still remains unclear. The tumor microenvironment has emerged as an important component contributing to DC malfunction. In this review we will discuss the potential role of tumor microenvironment in DC dysfunction.
European Urology Supplements, 2002
Journal of Bacteriology, Nov 1, 2001
Using immunofluorescence microscopy and a fusion of a cold shock protein (CSP), CspB, to green fl... more Using immunofluorescence microscopy and a fusion of a cold shock protein (CSP), CspB, to green fluorescent protein (GFP), we showed that in growing cells Bacillus subtilis CSPs specifically localize to cytosolic regions surrounding the nucleoid. The subcellular localization of CSPs is influenced by the structure of the nucleoid. Decondensed chromosomes in smc mutant cells reduced the sizes of the regions in which CSPs localized, while cold shock-induced chromosome compaction was accompanied by an expansion of the space in which CSPs were present. As a control, histone-like protein HBsu localized to the nucleoids, while -galactosidase and GFP were detectable throughout the cell. After inhibition of translation, CspB-GFP was still present around the nucleoids in a manner similar to that in cold-shocked cells. However, in stationary-phase cells and after inhibition of transcription, CspB was distributed throughout the cell, indicating that specific localization of CspB depends on active transcription and is not due to simple exclusion from the nucleoid. Furthermore, we observed that nucleoids are more condensed and frequently abnormal in cspB cspC and cspB cspD doublemutant cells. This suggests that the function of CSPs affects chromosome structure, probably through coupling of transcription to translation, which is thought to decondense nucleoids. In addition, we found that cspB cspD and cspB cspC double mutants are defective in sporulation, with a block at or before stage 0. Interestingly, CspB and CspC are depleted from the forespore compartment but not from the mother cell. In toto, our findings suggest that CSPs localize to zones of newly synthesized RNA, coupling transcription with initiation of translation.
The FASEB Journal, Aug 19, 2004
Recent evidence suggests that platelets are not only involved in haemostatic processes but also m... more Recent evidence suggests that platelets are not only involved in haemostatic processes but also modulate immune responses. As antigen-presenting cells (APC) are of crucial importance for the regulation of immunity, in this study we wanted to define the role of platelet factor 4 (PF-4) as one of the major platelet-derived chemokines on the transition of monocytes into APCs. Our experiments show that within 3 days PF-4 in conjunction with IL-4 induces a rapid differentiation of monocytes into APC. These PFAPC (PF-4/IL-4 differentiated APC) display unique phenotypical and functional characteristics setting them apart from macrophages and conventional dendritic cells. Functional studies revealed that PFAPC preferentially stimulated proliferation of lymphocytes and lytic NK activity while they induced only moderate cytokine responses. Beyond day 3 of differentiation, PFAPC became less immunostimulatory and maintained their capacity to phagocytose particulate material even after LPS-induced maturation. These experiments uncover a previously unknown role for the platelet-derived CXC-chemokine PF-4 in differentiation of human APC. Our data further support the newly discovered function of platelets in immunomodulation and provide new evidence for a rapid transition of monocytes into APC under the influence of inflammatory stimuli.
Journal of Thoracic Oncology, Aug 1, 2007
Interferons were the original prototype cytokine system discovered during research of the 20th ce... more Interferons were the original prototype cytokine system discovered during research of the 20th century. As the name suggests these were originally considered to be synthesised and secreted between cells. However, technological advancements since dictate processes involved in secreting these proteins can be extensively explained through both genetic and biochemical pathways comparatively clearer. Interferon (IFN) discovery occurred when genetic research was in its infancy. Simultaneous discovery by Franklin and Wilkins of deoxyribonucleic acid (DNA) structure and function occurred with Crick and Watson concurrently; however, two scientists Isaac and Lindemann described the first IFN in 1957. Technological advancement allows comparison, since many pathogens and genetic mutations can be factors in IFN regulation. Cancer cell regulation in research has long been central to host IFN synthesis and/or affected with differential IFN protein subunits defined further acting through 6 protein ...
Ebola virus is a zoonotic virus comprised of 6 different species designated within the family Fil... more Ebola virus is a zoonotic virus comprised of 6 different species designated within the family Filoviridae and genus Ebolavirus. The first recorded outbreak of an Ebola virus (EBOV) was in Yambuku, Zaire (ZEBOV) in 1976, followed by Sudan Ebola virus (SUBOV) later that year. Outbreaks have been increasing throughout the 21st century, and mortality rates can reach up to 90%. Such extraordinary virulence is evidenced with few pathogens, similarly with Marburg virus (MARV) that originated in Uganda and was first detected in Germany in 1967. The virulent nature of filovirus disease has established these related viruses as a formidable global concern. There are currently four types of Ebolaviridae species known to infect humans, with two more recently identified in other animals that are genomically different with respect to cellular pathogenesis or aetiology of disease. Recent advances into understanding the pathogenesis of filovirus disease infections have been remarkable, yet the immun...
Immuno, Apr 27, 2023
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Vaccines
The coronavirus disease 2019 (COVID-19) pandemic is caused by the severe acute respiratory syndro... more The coronavirus disease 2019 (COVID-19) pandemic is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, which is defined by its positive-sense single-stranded RNA (ssRNA) structure. It is in the order Nidovirales, suborder Coronaviridae, genus Betacoronavirus, and sub-genus Sarbecovirus (lineage B), together with two bat-derived strains with a 96% genomic homology with other bat coronaviruses (BatCoVand RaTG13). Thus far, two Alphacoronavirus strains, HCoV-229E and HCoV-NL63, along with five Betacoronaviruses, HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and SARS-CoV-2, have been recognized as human coronaviruses (HCoVs). SARS-CoV-2 has resulted in more than six million deaths worldwide since late 2019. The appearance of this novel virus is defined by its high and variable transmission rate (RT) and coexisting asymptomatic and symptomatic propagation within and across animal populations, which has a longer-lasting impact. Most current therapeutic methods a...
Journal of Clinical Oncology, 2007
21087 Background: Induction of antitumor immune responses requires adequate DC function. Well-doc... more 21087 Background: Induction of antitumor immune responses requires adequate DC function. Well-documented DC defects in cancer mediated through tumor-derived vascular endothelial growth factor (VEGF) may lead to tumor escape and limit efficacy of cancer vaccines. V-T with extracellular domains of VEGFR 1/ 2 coupled to Fc IgG1 binds all VEGF-A isoforms. Methods: To determine if inhibition of VEGF signaling improves immune responses, we evaluated 15 cancer pts treated with V-T (2.0–7.0 mg/kg) IV over 1 hr Q 2 wks on a phase I trial. To evaluate immune parameters, PBMC were collected prior to, days 15, 29, and 57 of V-T treatment. Ligand blockade was achieved in all patients. Mature DCs (myeloid and plasmacytoid subsets), and regulatory T cells (T regs) were characterized by expression pattern of CD11c, CD86, CD40, CCR7, CD83, CD123, CD4, CD25, and GITR. T cell function was assessed by allogeneic mixed leukocyte reaction (MLR) and proliferation to tetanus toxoid, influenza, or PHA. Resu...
Cancer Research, Apr 15, 2006
Proc Amer Assoc Cancer Res, Volume 47, 2006 4877 Abnormal differentiation of dendritic cells (DC)... more Proc Amer Assoc Cancer Res, Volume 47, 2006 4877 Abnormal differentiation of dendritic cells (DC) in cancer manifests in decreased presence and impaired function of mature DCs and the appearance of a larger number of immature myeloid cells (ImC) that are capable of suppressing antigen-specific T cells. Recently it becomes increasingly clear that success of immune intervention in cancer will depend on the ability to remove ImC and improve differentiation of DCs. Previous in vitro and in vivo studies in tumor-bearing mice suggested that all-trans-retinoic acid (ATRA) could improve DC differentiation and eliminate ImC. Here, we for the first time have tested the effect of ATRA on DCs and ImC in cancer patients. Eighteen patients with advanced stage renal cell carcinoma (RCC) were enrolled onto the study and received treatment with ATRA (50-150 mg/m2/day) for seven days. Seven days after completion of ATRA treatment patients started IL-2 therapy for five consecutive weeks. Peripheral blood was collected weekly. In parallel blood was collected from 16 patients that received IL-2 therapy alone. Control group comprised 7 healthy volunteers. Mononuclear cells (MNC) isolated at each time point were stored in liquid nitrogen. All samples from the same patient were analyzed simultaneously. After thawing MNC were cultured overnight and then were labeled with a cocktail of lineage specific antibodies (anti-CD3, CD19, CD56 and CD14), anti-HLA-DR antibody, anti-CD33 antibody, and either anti-CD86, anti-CD40, anti-CD83, or anti-CCR7 antibodies. ImC were defined as Lin negative, HLA-DR negative, CD33 positive cells. DCs were defined as lineage negative, HLA-DR positive cells. In addition, the presence of myeloid and plasmocytoid subsets of DCs was determined using anti-CD11c and anti-CD123 antibodies. Cells were evaluated by flow cytometry. The proportions of different populations of DCs were calculated. In addition the response of MNC to antigen (tetanus toxoid) and mitogen (PHA) was evaluated as well as the ability of DCs to stimulate allogeneic T cells. To date no adverse effect of the therapy was reported. This trial is at an early stage, however, the initial results are very encouraging. As expected almost all patients with metastatic RCC had increased level of ImC. ATRA treatment substantially decreased the number of ImC in more than 90% of them. In 60% of patients the presence of ImC was reduced to the control level. ATRA treatment substantially increased the proportion and functional activity of DCs. The presence of CD83+ or CD40+ mature DCs was also increased. These first results suggest that ATRA may substantially improve DC differentiation and eliminate ImC in cancer patients. It could be a valuable addition to different cancer immunotherapeutic strategies.
Since 2019, notable global viral outbreaks have occurred necessitating further research and healt... more Since 2019, notable global viral outbreaks have occurred necessitating further research and healthcare system investigations. Following the COVID—19 pandemic, an unexpected duality has occurred of SARS–CoV–2 and monkeypox virus (MPXV) infections. Monkeypox virus is of the Orthopoxviridae genus, belonging to the family Poxviridae. Zoonotic transmission (animal to human transmission) may occur. The Orthopoxviridae genus includes other Orthopoxviruses (OPXV) present in animal host reservoirs that include cowpox viruses (CPXV), vaccinia virus (VACV) and variola virus (VARV), with the latter being causal agent of smallpox and excessive mortality. The aim in this review is to present facts about MPXV specific pathogenesis, epidemiology, and immunology alongside historical perspectives. Monkeypox virus was rarely reported outside Africa before April 2000. Early research since 1796 contributed towards eradication of VARV leading to immunisation strategies. The World Health Organisation (WHO...
We have outlined the idea of creating a synthetic standardized convalescent plasma with assigned ... more We have outlined the idea of creating a synthetic standardized convalescent plasma with assigned neutralization capacity and a vaccine strategy using a multipeptide approach targeting the mucosal immune system.
Cancer Research, Apr 15, 2006
Proc Amer Assoc Cancer Res, Volume 47, 2006 4877 Abnormal differentiation of dendritic cells (DC)... more Proc Amer Assoc Cancer Res, Volume 47, 2006 4877 Abnormal differentiation of dendritic cells (DC) in cancer manifests in decreased presence and impaired function of mature DCs and the appearance of a larger number of immature myeloid cells (ImC) that are capable of suppressing antigen-specific T cells. Recently it becomes increasingly clear that success of immune intervention in cancer will depend on the ability to remove ImC and improve differentiation of DCs. Previous in vitro and in vivo studies in tumor-bearing mice suggested that all-trans-retinoic acid (ATRA) could improve DC differentiation and eliminate ImC. Here, we for the first time have tested the effect of ATRA on DCs and ImC in cancer patients. Eighteen patients with advanced stage renal cell carcinoma (RCC) were enrolled onto the study and received treatment with ATRA (50-150 mg/m2/day) for seven days. Seven days after completion of ATRA treatment patients started IL-2 therapy for five consecutive weeks. Peripheral blood was collected weekly. In parallel blood was collected from 16 patients that received IL-2 therapy alone. Control group comprised 7 healthy volunteers. Mononuclear cells (MNC) isolated at each time point were stored in liquid nitrogen. All samples from the same patient were analyzed simultaneously. After thawing MNC were cultured overnight and then were labeled with a cocktail of lineage specific antibodies (anti-CD3, CD19, CD56 and CD14), anti-HLA-DR antibody, anti-CD33 antibody, and either anti-CD86, anti-CD40, anti-CD83, or anti-CCR7 antibodies. ImC were defined as Lin negative, HLA-DR negative, CD33 positive cells. DCs were defined as lineage negative, HLA-DR positive cells. In addition, the presence of myeloid and plasmocytoid subsets of DCs was determined using anti-CD11c and anti-CD123 antibodies. Cells were evaluated by flow cytometry. The proportions of different populations of DCs were calculated. In addition the response of MNC to antigen (tetanus toxoid) and mitogen (PHA) was evaluated as well as the ability of DCs to stimulate allogeneic T cells. To date no adverse effect of the therapy was reported. This trial is at an early stage, however, the initial results are very encouraging. As expected almost all patients with metastatic RCC had increased level of ImC. ATRA treatment substantially decreased the number of ImC in more than 90% of them. In 60% of patients the presence of ImC was reduced to the control level. ATRA treatment substantially increased the proportion and functional activity of DCs. The presence of CD83+ or CD40+ mature DCs was also increased. These first results suggest that ATRA may substantially improve DC differentiation and eliminate ImC in cancer patients. It could be a valuable addition to different cancer immunotherapeutic strategies.
Nucleic Acids Research, 2002
CSDBase (http://www.chemie.uni-marburg.de/\~csdbase/) is an interactive Internet-embedded research... more CSDBase (http://www.chemie.uni-marburg.de/~csdbase/) is an interactive Internet-embedded research platform providing detailed information on proteins containing the cold shock domain (CSD). It consists of two separated database cores, one dedicated to CSD protein information, and one to provide a powerful resource to relevant literature with emphasis on the bacterial cold shock response. In addition to detailed protein information and useful cross links to other web sites, CSDBase contains computer-generated CSD structure models for most CSD-containing protein sequences available at NCBI non-redundant protein database at the time of CSDBase establishment. These models were calculated on the basis of known crystal and/or NMR structures using SWISS-MODEL and can be downloaded as PDB structure coordinate files for viewing and for manipulation with other software tools. CSDBase will be regularly updated and is organized in a compact form providing user friendly interfaces to both database cores which allow for easy data retrieval.
Clinical Cancer Research, Feb 1, 2006
The initial goal of this study was to test the immunologic and clinical effects of a new cancer v... more The initial goal of this study was to test the immunologic and clinical effects of a new cancer vaccine consisting of dendritic cells (DC) transduced with the full-length wild-type p53 gene delivered via an adenoviral vector in patients with extensive stage small cell lung cancer. Experimental Design: Twenty-nine patients with extensive stage small cell lung cancer were vaccinated repeatedly at 2-week intervals. Most of the patients received three immunizations. p53-specific responses were evaluated, and phenotype and function of Tcells, DCs, and immature myeloid cells were analyzed and correlated with antigen-specific immune responses. Objective clinical response to vaccination as well as subsequent chemotherapy was evaluated. Results: p53-specificTcell responses to vaccination were observed in 57.1% of patients. Immunologic responses to vaccination were positively associated with a moderate increase in the titer of antiadenovirus antibodies, and negatively with an accumulation of immature myeloid cells. One patient showed a clinical response to vaccination whereas most of the patients had disease progression. However, we observed a high rate of objective clinical responses to chemotherapy (61.9%) that immediately followed vaccination. Clinical response to subsequent chemotherapy was closely associated with induction of immunologic response to vaccination. Conclusions: This study provides clinical support for an emerging paradigm in cancer immunotherapy, wherein optimal use of vaccination might be more effective, not as a separate modality, but in direct combination with chemotherapy.
The coronavirus 2019 (COVID-19) pandemic was caused by a positive sense singlestranded RNA (ssRNA... more The coronavirus 2019 (COVID-19) pandemic was caused by a positive sense singlestranded RNA (ssRNA) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, other human coronaviruses (hCoVs) exist, of which Middle East Respiratory Syndrome (MERS) and SARS-CoV (SARS) showed higher mortality rates without causing a pandemic. As of December 2022, SARS-CoV-2 has resulted in over 6.6 million deaths worldwide through an array of acute to chronic pathologies. Historical pandemics include smallpox and influenza with efficacious therapeutics utilized to reduce overall disease burden. Therefore, immune system process analysis is required to compare innate and adaptive immune system interactions. Lymphatic system organs include bone marrow and thymus using a network of nodes throughout which white blood cells traverse glycolipid membranes utilizing cytokines and chemokine gradients that affect cell development, differentiation, proliferation, and migration processes as well as genetic factors affecting cell receptor expression.
Clinical Cancer Research, Aug 15, 2007
Induction of antitumor immune responses requires adequate function of dendritic cells. Dendritic ... more Induction of antitumor immune responses requires adequate function of dendritic cells. Dendritic cell defects in cancer patients have been implicated in tumor escape and the limited efficacy of cancer vaccines. Previous studies have shown that vascular endothelial growth factor (VEGF) plays a major role in abnormal dendritic cell differentiation and function in cancer. It has been proposed that inhibition of VEGF may result in improved immune responses. The goal of this study was to test this hypothesis. Experimental Design: Fifteen patients with refractory solid tumors were enrolled into a phase I clinical trial of VEGF-Trap. Phenotype and function of different subsets of mononuclear cells were measured before and at different time points after the start of treatment. Results: VEGF-Trap treatment did not affect the total population of dendritic cells, their myeloid or plasmacytoid subsets, myeloid-derived suppressor cells (MDSC), or regulatory T cells. It significantly increased the proportion of mature dendritic cells. However, that improvement was not associated with an overall increase in immune responses to various antigens and mitogens. A subset analysis revealed significant improvement in immune responses in patients who had no increase in the proportion of MDSC. An improvement in immune responses was absent in patients with an increase in the proportion of MDSC. Conclusions: Inhibition of VEGF signaling may improve differentiation of dendritic cells in cancer patients. However, it was not sufficient to improve immune responses. This shows multifaceted nature of immune deficiency and points out to the need for complex approach to modulation of immune reactivity in cancer.
Journal of Immunology, May 1, 2006
R753Q polymorphism compromises TLR2 signaling functions by altering TLR6-TLR2 hetero-dimerization... more R753Q polymorphism compromises TLR2 signaling functions by altering TLR6-TLR2 hetero-dimerization, TLR2 tyrosine phosphorylation and MyD88 recruitment (180.2)
Immunological Investigations, 2006
The fact that the immune response to cancer is compromised has been convincingly demonstrated in ... more The fact that the immune response to cancer is compromised has been convincingly demonstrated in murine tumor models as well as in cancer patients. The unresponsiveness of the host immune system is one of the major mechanisms of tumor escape as well as an important factor that limits the success of cancer immunotherapy. Inadequate function of professional antigen presenting cells dendritic cells (DC) in cancer is one of the major elements of compromised anti-tumor immune response. Despite substantial progress in recent years, the mechanism of inadequate DC function in cancer still remains unclear. The tumor microenvironment has emerged as an important component contributing to DC malfunction. In this review we will discuss the potential role of tumor microenvironment in DC dysfunction.
European Urology Supplements, 2002
Journal of Bacteriology, Nov 1, 2001
Using immunofluorescence microscopy and a fusion of a cold shock protein (CSP), CspB, to green fl... more Using immunofluorescence microscopy and a fusion of a cold shock protein (CSP), CspB, to green fluorescent protein (GFP), we showed that in growing cells Bacillus subtilis CSPs specifically localize to cytosolic regions surrounding the nucleoid. The subcellular localization of CSPs is influenced by the structure of the nucleoid. Decondensed chromosomes in smc mutant cells reduced the sizes of the regions in which CSPs localized, while cold shock-induced chromosome compaction was accompanied by an expansion of the space in which CSPs were present. As a control, histone-like protein HBsu localized to the nucleoids, while -galactosidase and GFP were detectable throughout the cell. After inhibition of translation, CspB-GFP was still present around the nucleoids in a manner similar to that in cold-shocked cells. However, in stationary-phase cells and after inhibition of transcription, CspB was distributed throughout the cell, indicating that specific localization of CspB depends on active transcription and is not due to simple exclusion from the nucleoid. Furthermore, we observed that nucleoids are more condensed and frequently abnormal in cspB cspC and cspB cspD doublemutant cells. This suggests that the function of CSPs affects chromosome structure, probably through coupling of transcription to translation, which is thought to decondense nucleoids. In addition, we found that cspB cspD and cspB cspC double mutants are defective in sporulation, with a block at or before stage 0. Interestingly, CspB and CspC are depleted from the forespore compartment but not from the mother cell. In toto, our findings suggest that CSPs localize to zones of newly synthesized RNA, coupling transcription with initiation of translation.
The FASEB Journal, Aug 19, 2004
Recent evidence suggests that platelets are not only involved in haemostatic processes but also m... more Recent evidence suggests that platelets are not only involved in haemostatic processes but also modulate immune responses. As antigen-presenting cells (APC) are of crucial importance for the regulation of immunity, in this study we wanted to define the role of platelet factor 4 (PF-4) as one of the major platelet-derived chemokines on the transition of monocytes into APCs. Our experiments show that within 3 days PF-4 in conjunction with IL-4 induces a rapid differentiation of monocytes into APC. These PFAPC (PF-4/IL-4 differentiated APC) display unique phenotypical and functional characteristics setting them apart from macrophages and conventional dendritic cells. Functional studies revealed that PFAPC preferentially stimulated proliferation of lymphocytes and lytic NK activity while they induced only moderate cytokine responses. Beyond day 3 of differentiation, PFAPC became less immunostimulatory and maintained their capacity to phagocytose particulate material even after LPS-induced maturation. These experiments uncover a previously unknown role for the platelet-derived CXC-chemokine PF-4 in differentiation of human APC. Our data further support the newly discovered function of platelets in immunomodulation and provide new evidence for a rapid transition of monocytes into APC under the influence of inflammatory stimuli.
Journal of Thoracic Oncology, Aug 1, 2007
Interferons were the original prototype cytokine system discovered during research of the 20th ce... more Interferons were the original prototype cytokine system discovered during research of the 20th century. As the name suggests these were originally considered to be synthesised and secreted between cells. However, technological advancements since dictate processes involved in secreting these proteins can be extensively explained through both genetic and biochemical pathways comparatively clearer. Interferon (IFN) discovery occurred when genetic research was in its infancy. Simultaneous discovery by Franklin and Wilkins of deoxyribonucleic acid (DNA) structure and function occurred with Crick and Watson concurrently; however, two scientists Isaac and Lindemann described the first IFN in 1957. Technological advancement allows comparison, since many pathogens and genetic mutations can be factors in IFN regulation. Cancer cell regulation in research has long been central to host IFN synthesis and/or affected with differential IFN protein subunits defined further acting through 6 protein ...
Ebola virus is a zoonotic virus comprised of 6 different species designated within the family Fil... more Ebola virus is a zoonotic virus comprised of 6 different species designated within the family Filoviridae and genus Ebolavirus. The first recorded outbreak of an Ebola virus (EBOV) was in Yambuku, Zaire (ZEBOV) in 1976, followed by Sudan Ebola virus (SUBOV) later that year. Outbreaks have been increasing throughout the 21st century, and mortality rates can reach up to 90%. Such extraordinary virulence is evidenced with few pathogens, similarly with Marburg virus (MARV) that originated in Uganda and was first detected in Germany in 1967. The virulent nature of filovirus disease has established these related viruses as a formidable global concern. There are currently four types of Ebolaviridae species known to infect humans, with two more recently identified in other animals that are genomically different with respect to cellular pathogenesis or aetiology of disease. Recent advances into understanding the pathogenesis of filovirus disease infections have been remarkable, yet the immun...
Immuno, Apr 27, 2023
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Vaccines
The coronavirus disease 2019 (COVID-19) pandemic is caused by the severe acute respiratory syndro... more The coronavirus disease 2019 (COVID-19) pandemic is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, which is defined by its positive-sense single-stranded RNA (ssRNA) structure. It is in the order Nidovirales, suborder Coronaviridae, genus Betacoronavirus, and sub-genus Sarbecovirus (lineage B), together with two bat-derived strains with a 96% genomic homology with other bat coronaviruses (BatCoVand RaTG13). Thus far, two Alphacoronavirus strains, HCoV-229E and HCoV-NL63, along with five Betacoronaviruses, HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and SARS-CoV-2, have been recognized as human coronaviruses (HCoVs). SARS-CoV-2 has resulted in more than six million deaths worldwide since late 2019. The appearance of this novel virus is defined by its high and variable transmission rate (RT) and coexisting asymptomatic and symptomatic propagation within and across animal populations, which has a longer-lasting impact. Most current therapeutic methods a...
Journal of Clinical Oncology, 2007
21087 Background: Induction of antitumor immune responses requires adequate DC function. Well-doc... more 21087 Background: Induction of antitumor immune responses requires adequate DC function. Well-documented DC defects in cancer mediated through tumor-derived vascular endothelial growth factor (VEGF) may lead to tumor escape and limit efficacy of cancer vaccines. V-T with extracellular domains of VEGFR 1/ 2 coupled to Fc IgG1 binds all VEGF-A isoforms. Methods: To determine if inhibition of VEGF signaling improves immune responses, we evaluated 15 cancer pts treated with V-T (2.0–7.0 mg/kg) IV over 1 hr Q 2 wks on a phase I trial. To evaluate immune parameters, PBMC were collected prior to, days 15, 29, and 57 of V-T treatment. Ligand blockade was achieved in all patients. Mature DCs (myeloid and plasmacytoid subsets), and regulatory T cells (T regs) were characterized by expression pattern of CD11c, CD86, CD40, CCR7, CD83, CD123, CD4, CD25, and GITR. T cell function was assessed by allogeneic mixed leukocyte reaction (MLR) and proliferation to tetanus toxoid, influenza, or PHA. Resu...
Cancer Research, Apr 15, 2006
Proc Amer Assoc Cancer Res, Volume 47, 2006 4877 Abnormal differentiation of dendritic cells (DC)... more Proc Amer Assoc Cancer Res, Volume 47, 2006 4877 Abnormal differentiation of dendritic cells (DC) in cancer manifests in decreased presence and impaired function of mature DCs and the appearance of a larger number of immature myeloid cells (ImC) that are capable of suppressing antigen-specific T cells. Recently it becomes increasingly clear that success of immune intervention in cancer will depend on the ability to remove ImC and improve differentiation of DCs. Previous in vitro and in vivo studies in tumor-bearing mice suggested that all-trans-retinoic acid (ATRA) could improve DC differentiation and eliminate ImC. Here, we for the first time have tested the effect of ATRA on DCs and ImC in cancer patients. Eighteen patients with advanced stage renal cell carcinoma (RCC) were enrolled onto the study and received treatment with ATRA (50-150 mg/m2/day) for seven days. Seven days after completion of ATRA treatment patients started IL-2 therapy for five consecutive weeks. Peripheral blood was collected weekly. In parallel blood was collected from 16 patients that received IL-2 therapy alone. Control group comprised 7 healthy volunteers. Mononuclear cells (MNC) isolated at each time point were stored in liquid nitrogen. All samples from the same patient were analyzed simultaneously. After thawing MNC were cultured overnight and then were labeled with a cocktail of lineage specific antibodies (anti-CD3, CD19, CD56 and CD14), anti-HLA-DR antibody, anti-CD33 antibody, and either anti-CD86, anti-CD40, anti-CD83, or anti-CCR7 antibodies. ImC were defined as Lin negative, HLA-DR negative, CD33 positive cells. DCs were defined as lineage negative, HLA-DR positive cells. In addition, the presence of myeloid and plasmocytoid subsets of DCs was determined using anti-CD11c and anti-CD123 antibodies. Cells were evaluated by flow cytometry. The proportions of different populations of DCs were calculated. In addition the response of MNC to antigen (tetanus toxoid) and mitogen (PHA) was evaluated as well as the ability of DCs to stimulate allogeneic T cells. To date no adverse effect of the therapy was reported. This trial is at an early stage, however, the initial results are very encouraging. As expected almost all patients with metastatic RCC had increased level of ImC. ATRA treatment substantially decreased the number of ImC in more than 90% of them. In 60% of patients the presence of ImC was reduced to the control level. ATRA treatment substantially increased the proportion and functional activity of DCs. The presence of CD83+ or CD40+ mature DCs was also increased. These first results suggest that ATRA may substantially improve DC differentiation and eliminate ImC in cancer patients. It could be a valuable addition to different cancer immunotherapeutic strategies.