Babita Agrawal - Academia.edu (original) (raw)
Papers by Babita Agrawal
Cells
Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is a serious and devastating infectious... more Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is a serious and devastating infectious disease worldwide. Approximately a quarter of the world population harbors latent Mtb infection without pathological consequences. Exposure of immunocompetent healthy individuals with Mtb does not result in active disease in more than 90% individuals, suggesting a defining role of host immunity to prevent and/or clear early infection. However, innate immune stimulation strategies have been relatively underexplored for the treatment of tuberculosis. In this study, we used cell culture and mouse models to examine the role of a heat-killed form of a non-pathogenic microbe, Caulobacter crescentus (HKCC), in inducing innate immunity and limiting Mtb infection. We also examined the added benefits of a distinct chemo-immunotherapeutic strategy that incorporates concurrent treatments with low doses of a first-line drug isoniazid and HKCC. This therapeutic approach resulted in highly significant...
The Journal of Immunology
We have recently provided evidence that there is a natural immunization against human cancer-asso... more We have recently provided evidence that there is a natural immunization against human cancer-associated MUC-1 mucin epitopes during pregnancy by studying MUC-1 Ag-specific T cell lines established from multiparous women. Using this experimental model system, we now report that MUC-1 peptide-specific MHC class I-restricted CTLs can be generated in vitro using T cells from multiparous women stimulated with synthetic MUC-1 peptide-loaded, autologous APCs. The complexity of cytokines produced in response to the MUC-1 peptide by anti-MUC-1 T-cells was examined. IFN-gamma was generated by MUC-1-specific T cell lines in long term cultures, whereas in short term cultures, both IFN-gamma and IL-4 were produced. The presence of MUC-1-reactive T cells in multiparous women is consistent with their potential role in immune surveillance and provides a rationale for the use of certain synthetic MUC-1 peptides for active specific immunotherapy of human carcinomas.
Frontiers in Immunology
Severe acute respiratory syndrome virus-2 (SARS-CoV-2), the causative infectious agent of the COV... more Severe acute respiratory syndrome virus-2 (SARS-CoV-2), the causative infectious agent of the COVID-19 pandemic, has led to multiple (4-6) waves of infections worldwide during the past two years. The development of vaccines against SARS-CoV-2 has led to successful mass immunizations worldwide, mitigating the worldwide mortality due the pandemic to a great extent. Yet the evolution of new variants highlights a need to develop a universal vaccine which can prevent infections from all virulent SARS-CoV-2. Most of the current first generation COVID-19 vaccines are based on the Spike protein from the original Wuhan-hu-1 virus strain. It is encouraging that they still protect from serious illnesses, hospitalizations and mortality against a number of mutated viral strains, to varying degrees. Understanding the mechanisms by which these vaccines provide heterologous protection against multiple highly mutated variants can reveal strategies to develop a universal vaccine. In addition, many un...
Plastic and Reconstructive Surgery - Global Open, 2019
Cancer research, Jan 15, 1998
MHC class I molecules were isolated from the MUC1-positive human breast adenocarcinoma cell line ... more MHC class I molecules were isolated from the MUC1-positive human breast adenocarcinoma cell line MCF-7 by immunoaffinity using the panreactive anti-class I monoclonal antibodies (MAb) W6/32. Acid-eluted peptides from the class I molecules were separated twice by high-performance liquid chromatography and tested for reactivity with the MAb BCP8, which reacts with the minimal MUC1 core peptide sequence PDTRPA. A peak with strong and specific BCP8 reactivity was found in fractions eluting at 16.5-17.5 min. The protocol used for the MUC1+ pancreatic adenocarcinoma cell line CAPAN-1 (HLA.A2) was to perform sequential affinity purifications of class I molecules using MAb W6/32, followed by affinity purification of HLA.A2 molecules by the HLA.A2.1-specific MAb, MA2.1, and high-performance liquid chromatography fractionation of the acid-eluted material. A single peak with MAb BCP8 reactivity was noted at 18-19 min. The protocol for the MUC1+ breast adenocarcinoma cell line SKBr-3 (HLA.A11,B...
Nature Medicine, 1998
A number of adenocarcinomas abundantly express and secrete underglycosylated MUC1 mucin. Undergly... more A number of adenocarcinomas abundantly express and secrete underglycosylated MUC1 mucin. Underglycosylation exposes tandem repeat peptide sequences on cancer-associated MUC1 mucin that are normally cryptic. High levels of MUC1 mucin are correlated with a poor prognosis and immunosuppression in adenocarcinoma patients. In this report we show that cancer-associated MUC1 mucin, affinity-purified from ascites fluids of cancer patients, and synthetic tandem repeats of MUC1 mucin core peptide can suppress human T-cell proliferative responses. This MUC1 mucin-induced suppression of T-cell responses can be reversed by the addition of exogenous IL-2 or anti-CD28 monoclonal antibody. These results are consistent with other studies showing that lymphocytes present in the vicinity of tumor cells are anergic and can be reactivated with exogenous interleukin-2. Overcoming MUC1 mucin-induced immunosuppression with IL-2 combined with active specific immunotherapy might be an effective immunotherapeutic strategy against human adenocarcinomas.
International Immunology, 1998
Antigen-specific MHC class II-and class I-restricted helper and cytotoxic T cell responses are im... more Antigen-specific MHC class II-and class I-restricted helper and cytotoxic T cell responses are important anti-cancer immune responses. MUC1 mucin is a potentially important target for immunotherapy because of its high expression on most human adenocarcinomas. MUC1 peptidespecific type 1 T cell responses were generated in vitro using human peripheral blood lymphocytes (PBL), incubated with liposomes containing synthetic MUC1 lipopeptide antigen. Only two weekly stimulations with the liposomal MUC1 formulation led to the generation of potent anti-MUC1specific T cell proliferation as well as class I-restricted cytotoxic responses. Thus the use of PBL pulsed with liposome-encapsulated antigen provides an effective approach of rapidly generating effective antigen-presenting cell (APC) function as well as antigen specific T cells in vitro. It may be feasible to use this technology for the rapid and effective generation of APC and/or T cells as cellular vaccines for adenocarcinomas.
Proceedings
Chronic infection with the hepatitis C virus (HCV) afflicts 1%–3% of the world’s population and c... more Chronic infection with the hepatitis C virus (HCV) afflicts 1%–3% of the world’s population and can lead to serious and late-stage liver diseases. Developing a vaccine for HCV is challenging because the correlates of protection are uncertain. Host immune responses play an important role in the outcome of infection with HCV. They can lead to viral clearance and a positive outcome, or progression and severity of the chronic disease. Studies of natural immunity to HCV in humans have resulted in many enigmas. Extensive research in the past >25 years into understanding the immune responses against HCV have still resulted in many unanswered questions, implicating the role of unknown factors and events. Human beings are not immunologically naïve because they are continually exposed to various environmental microbes and antigens, creating large populations of memory T and B cells. This pool of memory T and B cells can cross-react against a new pathogen in an individual and thereby influe...
Frontiers in Immunology
The central paradigm of vaccination is to generate resistance to infection by a specific pathogen... more The central paradigm of vaccination is to generate resistance to infection by a specific pathogen when the vacinee is re-exposed to that pathogen. This paradigm is based on two fundamental characteristics of the adaptive immune system, specificity and memory. These characteristics come from the clonal specificity of T and B cells and the long-term survival of previously-encountered memory cells which can rapidly and specifically expand upon re-exposure to the same specific antigen. However, there is an increasing awareness of the concept, as well as experimental documentation of, heterologous immunity and cross-reactivity of adaptive immune lymphocytes in protection from infection. This awareness is supported by a number of human epidemiological studies in vaccine recipients and/or individuals naturally-resistant to certain infections, as well as studies in mouse models of infections, and indeed theoretical considerations regarding the disproportional repertoire of available T and B cell clonotypes compared to antigenic epitopes found on pathogens. Heterologous immunity can broaden the protective outcomes of vaccinations, and natural resistance to infections. Besides exogenous microbes/pathogens and/or vaccines, endogenous microbiota can also impact the outcomes of an infection and/or vaccination through heterologous immunity. Moreover, utilization of viral and/or bacterial vaccine vectors, capable of inducing heterologous immunity may also influence the natural course of many infections/diseases. This review article will briefly discuss these implications and redress the central dogma of specificity in the immune system.
Frontiers in Immunology
T lymphocytes are at the center of inducing an effective adaptive immune response and maintaining... more T lymphocytes are at the center of inducing an effective adaptive immune response and maintaining homeostasis. T cell responses are initiated through interactions between antigen presenting cells (APCs) and T cells. The type and strength of signals delivered through the T cell receptor (TCR) may modulate how the cells respond. The TCR-MHC (T cell receptor-major histocompatibility complex molecules) complex dictates the specificity, whereas co-stimulatory signals induced by interaction of various accessory cell surface molecules strengthen and optimize T cell responses. Multiple immune regulatory mechanisms brought about by co-inhibitory molecules expressed on T cells play a key role in orchestrating successful and non-damaging immunity. These co-inhibitory molecules are also referred to as initiators of immune checkpoints or co-inhibitory pathways. Knowledge of co-inhibitory pathways associated with activated T lymphocytes has allowed a better understanding of (a) the inflammatory and anti-inflammatory processes associated with infectious diseases and autoimmune diseases, and (b) mechanisms by which tumors evade immune attack. Many of these regulatory pathways are non-redundant and function in a highly concerted manner. Targeting them has provided effective approaches in treating cancer and autoimmune diseases. For this reason, it is valuable to identify any co-inhibitory molecules that affect these pathways. MUC1 mucin (CD227) has long been known to be expressed by epithelial cells and overexpressed by a multitude of adenocarcinomas. As long ago as 1998 we made a surprising discovery that MUC1 is also expressed by activated human T cells and we provided the first evidence of the role of MUC1 as a novel T cell regulator. Subsequent studies from different laboratories, as well as ours, supported an immuno-regulatory role of MUC1 in infections, inflammation, and autoimmunity that corroborated our original findings establishing MUC1 as a novel T cell regulatory molecule. In this article, we will discuss the experimental evidence supporting MUC1 as a putative regulatory molecule or a "checkpoint molecule" of T cells with implications as a novel biomarker and therapeutic target in chronic diseases such as autoimmunity, inflammation and cancer, and possibly infections.
Clinical and Translational Medicine
Transformation and growth of tumor cells are associated with profound alterations in neighbouring... more Transformation and growth of tumor cells are associated with profound alterations in neighbouring cells and their environment, together forming the tumor microenvironment (TME). The TME provides a conducive but complex milieu for the tumors to thrive while incapacitating the immune cells that home there as part of our natural immunosurveillance mechanism. The orchestration of this successful survival strategy by tumor cells is associated with exploitation of numerous metabolic and immune checkpoints, as well as metabolic reprogramming in the tumor cells. Together these form an intricate network of feedback mechanisms that favor the growing tumor. In addition, an ecosystem of microbiota, proximal or distal to tumors, influences the successful survival or elimination of tumor cells mediated by immune cells. Discovery and clinical application of immune checkpoint inhibitors (ICIs) i.e., monoclonal antibodies (mAbs) blocking specific immune checkpoints CTLA-4 and PD-1/PD-L1, have revolutionized therapy of various cancers. However, they are still associated with limited response rates, severe immune-related adverse events, development of resistance, and more serious exacerbation of cancer progression termed hyper-progressive disease. Checkpoint inhibitors only represent a milestone and not the finish-line in the quest for treating and curing cancer. Efforts are underway to investigate and develop inhibitors of other immune as well as metabolic checkpoint molecules. Future therapy for various cancers is projected to target immune and metabolic checkpoints and the microbiota together.
Cells
Host immune responses play an important role in the outcome of infection with hepatitis C virus (... more Host immune responses play an important role in the outcome of infection with hepatitis C virus (HCV). They can lead to viral clearance and a positive outcome, or progression and severity of chronic disease. Extensive research in the past >25 years into understanding the immune responses against HCV have still resulted in many unanswered questions implicating a role for unknown factors and events. In our earlier studies, we made a surprising discovery that peptides derived from structural and non-structural proteins of HCV have substantial amino acid sequence homologies with various proteins of adenoviruses and that immunizing mice with a non-replicating, non-recombinant adenovirus vector leads to induction of a robust cross-reactive cellular and humoral response against various HCV antigens. In this work, we further demonstrate antibody cross-reactivity between Ad and HCV in vivo. We also extend this observation to show that recombinant adenoviruses containing antigens from unre...
Adenoviruses [Working Title]
Adenoviruses are one of the most genetically diverse DNA viruses and cause non-lifethreatening in... more Adenoviruses are one of the most genetically diverse DNA viruses and cause non-lifethreatening infections in the ocular, respiratory, or gastrointestinal epithelium of a diverse range of hosts. Adenoviruses are excellent vectors for delivering genes or vaccine antigens to the target host tissues and are being tested in several vaccine and gene therapy studies. Adenovirus-based vectors offer several advantages over other viral vectors such as broad range of tissue tropism, well-characterized genome, ease of genetic manipulation including acceptance of large transgene DNA insertions, inherent adjuvant properties, ability to induce robust transgene-specific T cell and antibody responses, non-replicative nature in host, and ease of production at large scale. However, several studies have highlighted major drawbacks to using adenovirus as vaccine and gene therapy vectors. These include pre-existing immunity in humans, inflammatory responses, sequestering of the vector to liver and spleen, and immunodominance of the vector genes over transgenes. In the same vein, recently discovered protein sequence homology and heterologous immunity between adenoviruses and hepatitis C virus have significant implications in the use of adenoviral vectors for vaccine development, especially for hepatitis C virus. This chapter focuses on the current scope and challenges in using adenoviral vector-based vaccines and gene therapies.
Frontiers in immunology, 2018
Tuberculosis (TB), an infectious disease caused by (), kills 5,000 people per day globally. Rapid... more Tuberculosis (TB), an infectious disease caused by (), kills 5,000 people per day globally. Rapid development and spread of various multi drug-resistant strains of emphasize that an effective vaccine is still the most cost-effectives and efficient way of controlling and eradicating TB. Bacillus Calmette-Guerin (BCG), the only licensed TB vaccine, still remains the most widely administered human vaccine, but is inefficient in protecting from pulmonary TB in adults. The protective immunity afforded by BCG is thought to wane with time and considered to last only through adolescent years. Heterologous boosting of BCG-primed immune responses using a subunit vaccine represents a promising vaccination approach to promote strong cellular responses against . In our earlier studies, we discovered lipopeptides of ESAT-6 antigen with strong potential as a subunit vaccine candidate. Here, we have investigated that potential as a booster to BCG vaccine in both a pre-exposure preventive vaccine an...
Frontiers in immunology, 2018
Tuberculosis (TB) is a highly contagious infection and devastating chronic disease, causing 10.4 ... more Tuberculosis (TB) is a highly contagious infection and devastating chronic disease, causing 10.4 million new infections and 1.8 million deaths every year globally. Efforts to control and eradicate TB are hampered by the rapid emergence of drug resistance and limited efficacy of the only available vaccine, BCG. Immunological events in the airways and lungs are of major importance in determining whether exposure to () results in successful infection or protective immunity. Several studies have demonstrated that the host microbiota is in constant contact with the immune system, and thus continually directs the nature of immune responses occurring during new infections. However, little is known about its role in the eventual outcome of the mycobacterial infection. In this review, we highlight the changes in microbial composition in the respiratory tract and gut that have been linked to the alteration of immune responses, and to the risk, prevention, and treatment of TB. In addition, we ...
International journal of molecular sciences, Jan 27, 2017
Chronic infection with hepatitis C virus (HCV) afflicts 3% of the world's population and can ... more Chronic infection with hepatitis C virus (HCV) afflicts 3% of the world's population and can lead to serious and late-stage liver diseases. Developing a vaccine for HCV is challenging because the correlates of protection are uncertain and traditional vaccine approaches do not work. Studies of natural immunity to HCV in humans have resulted in many enigmas. Human beings are not immunologically naïve because they are continually exposed to various environmental microbes and antigens, creating large populations of memory T cells. Heterologous immunity occurs when this pool of memory T cells cross-react against a new pathogen in an individual. Such heterologous immunity could influence the outcome when an individual is infected by a pathogen. We have recently made an unexpected finding that adenoviruses, a common environmental pathogen and an experimental vaccine vector, can induce robust cross-reactive immune responses against multiple antigens of HCV. Our unique finding of previou...
Vaccine, Nov 29, 2016
Mycobacterium tuberculosis (Mtb), the bacterial cause of tuberculosis, is a leading infectious ag... more Mycobacterium tuberculosis (Mtb), the bacterial cause of tuberculosis, is a leading infectious agent worldwide. The development of a new vaccine against Mtb is essential to control global spread of tuberculosis, since the current vaccine BCG is not very effective and antibiotic resistance is a serious, burgeoning problem. ESAT-6 is a secreted protein of Mtb, which is absent in BCG but has been implicated in inducing protective immunity against Mtb. Peptide based subunit vaccines are attractive due to their safety and high specificity in eliciting immune responses, but small synthetic peptides are usually not very immunogenic. We have designed a novel subunit vaccine for Mtb by using simple lipid (palmitic acid) modified derivatives of peptides from ESAT-6 protein corresponding to dominant human T cell epitopes and examined their ability to stimulate protective immunity against Mtb by intranasal and subcutaneous immunization in mice. We also investigated how individual TLR agonists a...
Cells
Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is a serious and devastating infectious... more Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is a serious and devastating infectious disease worldwide. Approximately a quarter of the world population harbors latent Mtb infection without pathological consequences. Exposure of immunocompetent healthy individuals with Mtb does not result in active disease in more than 90% individuals, suggesting a defining role of host immunity to prevent and/or clear early infection. However, innate immune stimulation strategies have been relatively underexplored for the treatment of tuberculosis. In this study, we used cell culture and mouse models to examine the role of a heat-killed form of a non-pathogenic microbe, Caulobacter crescentus (HKCC), in inducing innate immunity and limiting Mtb infection. We also examined the added benefits of a distinct chemo-immunotherapeutic strategy that incorporates concurrent treatments with low doses of a first-line drug isoniazid and HKCC. This therapeutic approach resulted in highly significant...
The Journal of Immunology
We have recently provided evidence that there is a natural immunization against human cancer-asso... more We have recently provided evidence that there is a natural immunization against human cancer-associated MUC-1 mucin epitopes during pregnancy by studying MUC-1 Ag-specific T cell lines established from multiparous women. Using this experimental model system, we now report that MUC-1 peptide-specific MHC class I-restricted CTLs can be generated in vitro using T cells from multiparous women stimulated with synthetic MUC-1 peptide-loaded, autologous APCs. The complexity of cytokines produced in response to the MUC-1 peptide by anti-MUC-1 T-cells was examined. IFN-gamma was generated by MUC-1-specific T cell lines in long term cultures, whereas in short term cultures, both IFN-gamma and IL-4 were produced. The presence of MUC-1-reactive T cells in multiparous women is consistent with their potential role in immune surveillance and provides a rationale for the use of certain synthetic MUC-1 peptides for active specific immunotherapy of human carcinomas.
Frontiers in Immunology
Severe acute respiratory syndrome virus-2 (SARS-CoV-2), the causative infectious agent of the COV... more Severe acute respiratory syndrome virus-2 (SARS-CoV-2), the causative infectious agent of the COVID-19 pandemic, has led to multiple (4-6) waves of infections worldwide during the past two years. The development of vaccines against SARS-CoV-2 has led to successful mass immunizations worldwide, mitigating the worldwide mortality due the pandemic to a great extent. Yet the evolution of new variants highlights a need to develop a universal vaccine which can prevent infections from all virulent SARS-CoV-2. Most of the current first generation COVID-19 vaccines are based on the Spike protein from the original Wuhan-hu-1 virus strain. It is encouraging that they still protect from serious illnesses, hospitalizations and mortality against a number of mutated viral strains, to varying degrees. Understanding the mechanisms by which these vaccines provide heterologous protection against multiple highly mutated variants can reveal strategies to develop a universal vaccine. In addition, many un...
Plastic and Reconstructive Surgery - Global Open, 2019
Cancer research, Jan 15, 1998
MHC class I molecules were isolated from the MUC1-positive human breast adenocarcinoma cell line ... more MHC class I molecules were isolated from the MUC1-positive human breast adenocarcinoma cell line MCF-7 by immunoaffinity using the panreactive anti-class I monoclonal antibodies (MAb) W6/32. Acid-eluted peptides from the class I molecules were separated twice by high-performance liquid chromatography and tested for reactivity with the MAb BCP8, which reacts with the minimal MUC1 core peptide sequence PDTRPA. A peak with strong and specific BCP8 reactivity was found in fractions eluting at 16.5-17.5 min. The protocol used for the MUC1+ pancreatic adenocarcinoma cell line CAPAN-1 (HLA.A2) was to perform sequential affinity purifications of class I molecules using MAb W6/32, followed by affinity purification of HLA.A2 molecules by the HLA.A2.1-specific MAb, MA2.1, and high-performance liquid chromatography fractionation of the acid-eluted material. A single peak with MAb BCP8 reactivity was noted at 18-19 min. The protocol for the MUC1+ breast adenocarcinoma cell line SKBr-3 (HLA.A11,B...
Nature Medicine, 1998
A number of adenocarcinomas abundantly express and secrete underglycosylated MUC1 mucin. Undergly... more A number of adenocarcinomas abundantly express and secrete underglycosylated MUC1 mucin. Underglycosylation exposes tandem repeat peptide sequences on cancer-associated MUC1 mucin that are normally cryptic. High levels of MUC1 mucin are correlated with a poor prognosis and immunosuppression in adenocarcinoma patients. In this report we show that cancer-associated MUC1 mucin, affinity-purified from ascites fluids of cancer patients, and synthetic tandem repeats of MUC1 mucin core peptide can suppress human T-cell proliferative responses. This MUC1 mucin-induced suppression of T-cell responses can be reversed by the addition of exogenous IL-2 or anti-CD28 monoclonal antibody. These results are consistent with other studies showing that lymphocytes present in the vicinity of tumor cells are anergic and can be reactivated with exogenous interleukin-2. Overcoming MUC1 mucin-induced immunosuppression with IL-2 combined with active specific immunotherapy might be an effective immunotherapeutic strategy against human adenocarcinomas.
International Immunology, 1998
Antigen-specific MHC class II-and class I-restricted helper and cytotoxic T cell responses are im... more Antigen-specific MHC class II-and class I-restricted helper and cytotoxic T cell responses are important anti-cancer immune responses. MUC1 mucin is a potentially important target for immunotherapy because of its high expression on most human adenocarcinomas. MUC1 peptidespecific type 1 T cell responses were generated in vitro using human peripheral blood lymphocytes (PBL), incubated with liposomes containing synthetic MUC1 lipopeptide antigen. Only two weekly stimulations with the liposomal MUC1 formulation led to the generation of potent anti-MUC1specific T cell proliferation as well as class I-restricted cytotoxic responses. Thus the use of PBL pulsed with liposome-encapsulated antigen provides an effective approach of rapidly generating effective antigen-presenting cell (APC) function as well as antigen specific T cells in vitro. It may be feasible to use this technology for the rapid and effective generation of APC and/or T cells as cellular vaccines for adenocarcinomas.
Proceedings
Chronic infection with the hepatitis C virus (HCV) afflicts 1%–3% of the world’s population and c... more Chronic infection with the hepatitis C virus (HCV) afflicts 1%–3% of the world’s population and can lead to serious and late-stage liver diseases. Developing a vaccine for HCV is challenging because the correlates of protection are uncertain. Host immune responses play an important role in the outcome of infection with HCV. They can lead to viral clearance and a positive outcome, or progression and severity of the chronic disease. Studies of natural immunity to HCV in humans have resulted in many enigmas. Extensive research in the past >25 years into understanding the immune responses against HCV have still resulted in many unanswered questions, implicating the role of unknown factors and events. Human beings are not immunologically naïve because they are continually exposed to various environmental microbes and antigens, creating large populations of memory T and B cells. This pool of memory T and B cells can cross-react against a new pathogen in an individual and thereby influe...
Frontiers in Immunology
The central paradigm of vaccination is to generate resistance to infection by a specific pathogen... more The central paradigm of vaccination is to generate resistance to infection by a specific pathogen when the vacinee is re-exposed to that pathogen. This paradigm is based on two fundamental characteristics of the adaptive immune system, specificity and memory. These characteristics come from the clonal specificity of T and B cells and the long-term survival of previously-encountered memory cells which can rapidly and specifically expand upon re-exposure to the same specific antigen. However, there is an increasing awareness of the concept, as well as experimental documentation of, heterologous immunity and cross-reactivity of adaptive immune lymphocytes in protection from infection. This awareness is supported by a number of human epidemiological studies in vaccine recipients and/or individuals naturally-resistant to certain infections, as well as studies in mouse models of infections, and indeed theoretical considerations regarding the disproportional repertoire of available T and B cell clonotypes compared to antigenic epitopes found on pathogens. Heterologous immunity can broaden the protective outcomes of vaccinations, and natural resistance to infections. Besides exogenous microbes/pathogens and/or vaccines, endogenous microbiota can also impact the outcomes of an infection and/or vaccination through heterologous immunity. Moreover, utilization of viral and/or bacterial vaccine vectors, capable of inducing heterologous immunity may also influence the natural course of many infections/diseases. This review article will briefly discuss these implications and redress the central dogma of specificity in the immune system.
Frontiers in Immunology
T lymphocytes are at the center of inducing an effective adaptive immune response and maintaining... more T lymphocytes are at the center of inducing an effective adaptive immune response and maintaining homeostasis. T cell responses are initiated through interactions between antigen presenting cells (APCs) and T cells. The type and strength of signals delivered through the T cell receptor (TCR) may modulate how the cells respond. The TCR-MHC (T cell receptor-major histocompatibility complex molecules) complex dictates the specificity, whereas co-stimulatory signals induced by interaction of various accessory cell surface molecules strengthen and optimize T cell responses. Multiple immune regulatory mechanisms brought about by co-inhibitory molecules expressed on T cells play a key role in orchestrating successful and non-damaging immunity. These co-inhibitory molecules are also referred to as initiators of immune checkpoints or co-inhibitory pathways. Knowledge of co-inhibitory pathways associated with activated T lymphocytes has allowed a better understanding of (a) the inflammatory and anti-inflammatory processes associated with infectious diseases and autoimmune diseases, and (b) mechanisms by which tumors evade immune attack. Many of these regulatory pathways are non-redundant and function in a highly concerted manner. Targeting them has provided effective approaches in treating cancer and autoimmune diseases. For this reason, it is valuable to identify any co-inhibitory molecules that affect these pathways. MUC1 mucin (CD227) has long been known to be expressed by epithelial cells and overexpressed by a multitude of adenocarcinomas. As long ago as 1998 we made a surprising discovery that MUC1 is also expressed by activated human T cells and we provided the first evidence of the role of MUC1 as a novel T cell regulator. Subsequent studies from different laboratories, as well as ours, supported an immuno-regulatory role of MUC1 in infections, inflammation, and autoimmunity that corroborated our original findings establishing MUC1 as a novel T cell regulatory molecule. In this article, we will discuss the experimental evidence supporting MUC1 as a putative regulatory molecule or a "checkpoint molecule" of T cells with implications as a novel biomarker and therapeutic target in chronic diseases such as autoimmunity, inflammation and cancer, and possibly infections.
Clinical and Translational Medicine
Transformation and growth of tumor cells are associated with profound alterations in neighbouring... more Transformation and growth of tumor cells are associated with profound alterations in neighbouring cells and their environment, together forming the tumor microenvironment (TME). The TME provides a conducive but complex milieu for the tumors to thrive while incapacitating the immune cells that home there as part of our natural immunosurveillance mechanism. The orchestration of this successful survival strategy by tumor cells is associated with exploitation of numerous metabolic and immune checkpoints, as well as metabolic reprogramming in the tumor cells. Together these form an intricate network of feedback mechanisms that favor the growing tumor. In addition, an ecosystem of microbiota, proximal or distal to tumors, influences the successful survival or elimination of tumor cells mediated by immune cells. Discovery and clinical application of immune checkpoint inhibitors (ICIs) i.e., monoclonal antibodies (mAbs) blocking specific immune checkpoints CTLA-4 and PD-1/PD-L1, have revolutionized therapy of various cancers. However, they are still associated with limited response rates, severe immune-related adverse events, development of resistance, and more serious exacerbation of cancer progression termed hyper-progressive disease. Checkpoint inhibitors only represent a milestone and not the finish-line in the quest for treating and curing cancer. Efforts are underway to investigate and develop inhibitors of other immune as well as metabolic checkpoint molecules. Future therapy for various cancers is projected to target immune and metabolic checkpoints and the microbiota together.
Cells
Host immune responses play an important role in the outcome of infection with hepatitis C virus (... more Host immune responses play an important role in the outcome of infection with hepatitis C virus (HCV). They can lead to viral clearance and a positive outcome, or progression and severity of chronic disease. Extensive research in the past >25 years into understanding the immune responses against HCV have still resulted in many unanswered questions implicating a role for unknown factors and events. In our earlier studies, we made a surprising discovery that peptides derived from structural and non-structural proteins of HCV have substantial amino acid sequence homologies with various proteins of adenoviruses and that immunizing mice with a non-replicating, non-recombinant adenovirus vector leads to induction of a robust cross-reactive cellular and humoral response against various HCV antigens. In this work, we further demonstrate antibody cross-reactivity between Ad and HCV in vivo. We also extend this observation to show that recombinant adenoviruses containing antigens from unre...
Adenoviruses [Working Title]
Adenoviruses are one of the most genetically diverse DNA viruses and cause non-lifethreatening in... more Adenoviruses are one of the most genetically diverse DNA viruses and cause non-lifethreatening infections in the ocular, respiratory, or gastrointestinal epithelium of a diverse range of hosts. Adenoviruses are excellent vectors for delivering genes or vaccine antigens to the target host tissues and are being tested in several vaccine and gene therapy studies. Adenovirus-based vectors offer several advantages over other viral vectors such as broad range of tissue tropism, well-characterized genome, ease of genetic manipulation including acceptance of large transgene DNA insertions, inherent adjuvant properties, ability to induce robust transgene-specific T cell and antibody responses, non-replicative nature in host, and ease of production at large scale. However, several studies have highlighted major drawbacks to using adenovirus as vaccine and gene therapy vectors. These include pre-existing immunity in humans, inflammatory responses, sequestering of the vector to liver and spleen, and immunodominance of the vector genes over transgenes. In the same vein, recently discovered protein sequence homology and heterologous immunity between adenoviruses and hepatitis C virus have significant implications in the use of adenoviral vectors for vaccine development, especially for hepatitis C virus. This chapter focuses on the current scope and challenges in using adenoviral vector-based vaccines and gene therapies.
Frontiers in immunology, 2018
Tuberculosis (TB), an infectious disease caused by (), kills 5,000 people per day globally. Rapid... more Tuberculosis (TB), an infectious disease caused by (), kills 5,000 people per day globally. Rapid development and spread of various multi drug-resistant strains of emphasize that an effective vaccine is still the most cost-effectives and efficient way of controlling and eradicating TB. Bacillus Calmette-Guerin (BCG), the only licensed TB vaccine, still remains the most widely administered human vaccine, but is inefficient in protecting from pulmonary TB in adults. The protective immunity afforded by BCG is thought to wane with time and considered to last only through adolescent years. Heterologous boosting of BCG-primed immune responses using a subunit vaccine represents a promising vaccination approach to promote strong cellular responses against . In our earlier studies, we discovered lipopeptides of ESAT-6 antigen with strong potential as a subunit vaccine candidate. Here, we have investigated that potential as a booster to BCG vaccine in both a pre-exposure preventive vaccine an...
Frontiers in immunology, 2018
Tuberculosis (TB) is a highly contagious infection and devastating chronic disease, causing 10.4 ... more Tuberculosis (TB) is a highly contagious infection and devastating chronic disease, causing 10.4 million new infections and 1.8 million deaths every year globally. Efforts to control and eradicate TB are hampered by the rapid emergence of drug resistance and limited efficacy of the only available vaccine, BCG. Immunological events in the airways and lungs are of major importance in determining whether exposure to () results in successful infection or protective immunity. Several studies have demonstrated that the host microbiota is in constant contact with the immune system, and thus continually directs the nature of immune responses occurring during new infections. However, little is known about its role in the eventual outcome of the mycobacterial infection. In this review, we highlight the changes in microbial composition in the respiratory tract and gut that have been linked to the alteration of immune responses, and to the risk, prevention, and treatment of TB. In addition, we ...
International journal of molecular sciences, Jan 27, 2017
Chronic infection with hepatitis C virus (HCV) afflicts 3% of the world's population and can ... more Chronic infection with hepatitis C virus (HCV) afflicts 3% of the world's population and can lead to serious and late-stage liver diseases. Developing a vaccine for HCV is challenging because the correlates of protection are uncertain and traditional vaccine approaches do not work. Studies of natural immunity to HCV in humans have resulted in many enigmas. Human beings are not immunologically naïve because they are continually exposed to various environmental microbes and antigens, creating large populations of memory T cells. Heterologous immunity occurs when this pool of memory T cells cross-react against a new pathogen in an individual. Such heterologous immunity could influence the outcome when an individual is infected by a pathogen. We have recently made an unexpected finding that adenoviruses, a common environmental pathogen and an experimental vaccine vector, can induce robust cross-reactive immune responses against multiple antigens of HCV. Our unique finding of previou...
Vaccine, Nov 29, 2016
Mycobacterium tuberculosis (Mtb), the bacterial cause of tuberculosis, is a leading infectious ag... more Mycobacterium tuberculosis (Mtb), the bacterial cause of tuberculosis, is a leading infectious agent worldwide. The development of a new vaccine against Mtb is essential to control global spread of tuberculosis, since the current vaccine BCG is not very effective and antibiotic resistance is a serious, burgeoning problem. ESAT-6 is a secreted protein of Mtb, which is absent in BCG but has been implicated in inducing protective immunity against Mtb. Peptide based subunit vaccines are attractive due to their safety and high specificity in eliciting immune responses, but small synthetic peptides are usually not very immunogenic. We have designed a novel subunit vaccine for Mtb by using simple lipid (palmitic acid) modified derivatives of peptides from ESAT-6 protein corresponding to dominant human T cell epitopes and examined their ability to stimulate protective immunity against Mtb by intranasal and subcutaneous immunization in mice. We also investigated how individual TLR agonists a...