Previous studies from our laboratory have shown an important role for B cells in the development ... more Previous studies from our laboratory have shown an important role for B cells in the development of Ag‐specific Th2 cells during a polarized Th2‐type response. In this study we examined the role of B cell in host protection to a nematode parasite, Heligmosomoides polygyrus (Hp). Hp is characterized by chronic infection following primary inoculation, but following drug‐induced worm clearance, secondary inoculation triggers a host protective memory Th2‐type response resulting in worm clearance. B cell deficient JhD and control WT mice were orally inoculated with Hp, followed by anti‐helminthic drug treatment on day 14, and one month later challenged with Hp. Compared to WT mice, JhD mice were much more susceptible to Hp infection with high numbers of worms. B cell deficiency did not affect T cell activation, IL‐4 and IL‐13 production by CD4 T cells in mesenteric lymph nodes, and alternatively activated macrophage activation in granulomas surrounding developing larvae in the submucosa....
Despite the promising clinical benefit of targeted and immune checkpoint blocking therapeutics, c... more Despite the promising clinical benefit of targeted and immune checkpoint blocking therapeutics, current strategies have limited success in breast cancer, indicating that additional inhibitory pathways are required to complement existing therapeutics. TAM receptors (Tyro-3, Axl, and Mertk) are often correlated with poor prognosis because of their capacities to sustain an immunosuppressive environment. Here, we ablate Axl on tumor cells using CRISPR/Cas9 gene editing, and by targeting Mertk in the tumor microenvironment (TME), we observed distinct functions of TAM as oncogenic kinases, as well as inhibitory immune receptors. Depletion of Axl suppressed cell intrinsic oncogenic properties, decreased tumor growth, reduced the incidence of lung metastasis and increased overall survival of mice when injected into mammary fat pad of syngeneic mice, and demonstrated synergy when combined with anti-PD-1 therapy. Blockade of Mertk function on macrophages decreased efferocytosis, altered the c...
More than 2 billion people worldwide are infected with helminths. Thus, it is possible for indivi... more More than 2 billion people worldwide are infected with helminths. Thus, it is possible for individuals to experience concomitant infection with helminth and intracellular microbes. Although the helminth-induced type 2 response can suppress type 1 proinflammatory responses required for the immunity against intracellular pathogens in the context of a coinfection, conflicting evidence suggest that helminth infection can enhance antimicrobial immunity. Using a coinfection model with the intestinal helminth Heligmosomoides polygyrus followed by infection with Toxoplasma gondii in Mus Musculus, we showed that the complex and dynamic effect of helminth infection is highly suppressive during the innate phase (days 0–3) of T. gondii infection and less stringent during the acute phase (d10). Helminth coinfection had a strong suppressive effect on the neutrophil, monocytic, and early IFN-γ/IL-12 responses. The IFN-γ response was later restored by compensatory production from T cells despite de...
CD4+ T cells are able to respond to various pathogens by differentiating into highly polarized T ... more CD4+ T cells are able to respond to various pathogens by differentiating into highly polarized T helper effector (Th) cells that regulate distinct immune responses. Bacteria and viruses can elicit a Th1 response and most helminth parasites can induce a Th2 response. Although, dendritic cells (DCs) are the most potent activators of naïve T cells in vitro, it remains unclear which cell population is most important under in vivo conditions to cause the polarization into effector groups. Naïve CD4+ T cells reside in T cell areas of secondary lymphoid organs and DC’s are the predominant MHC-II expressing cells in the T cell areas. To examine in vivo what antigen presenting cells (APCs) and accessory cells are associated with early stages of the Th2 response C57BL/6 mice received a subcutaneous ear injection in the context of an infectious helminth infection or Th1 inducing agent either in the presence or absence of Ealpha peptide. Local draining lymph nodes were harvested and flow cyto...
Regions of the world with high incidence of Tuberculosis (TB) are also endemic for helminthic dis... more Regions of the world with high incidence of Tuberculosis (TB) are also endemic for helminthic diseases. Helminthic infection elicits a profound Th2 immune response, which may alter theTh1 response necessary for the protection to TB. The impactof Th2 responses on the protective immune response elicited to TB is poorly understood. We co-infected BALB/c mice with the nematode Nippostrongylus brasiliensis (Nb) followed by virulent Erdman strain of Mtb via aerosolization. At 4 and 7 weeks post-Mtb infection, co-infected mice displayed significantly higher bacterial burden compared to mice infected with Mtb alone. Furthermore, the enhanced disease progression was accompanied by a shift in the Mtb-induced Th1 response to a Th2 response in the co-infected mice as demonstrated by an increase in Th2 cytokines IL-4 and IL-10. Taken together, theseresults demonstrate that helminth infection alters the ability of the host to mount an effective immune response to TB and modulates the course of tu...
Previous studies have suggested that resistin-like molecule beta (RELM-beta) contributes to prote... more Previous studies have suggested that resistin-like molecule beta (RELM-beta) contributes to protective immunity against intestinal nematode parasites by directly interfering with adult worm feeding in the lumen. Other studies have suggested that RELM-beta may also function in the mucosal milieu by regulating Th1/Th2 cytokine production. In our studies, we examined the development of the memory Th2-type response to the murine intestinal nematode parasite, Heligmosomoides polygyrus (Hp). Mice were inoculated with Hp, drug-cleared at day 14, and several weeks later given an Hp secondary inoculation. Consistent with previous studies, adult worm burden was increased in Hp inoculated RELM-beta KO compared to inoculated WT controls. Analysis of cytokine gene (RT-PCR) and protein (ELISPOT) expression in draining mesenteric lymph nodes (MLNs) showed reductions in Th2 cytokine levels in RELM-beta KO compared to WT mice at day 7 after Hp secondary inoculation. At this time point spleen weight ...
Intestinal helminth parasites express excretory/secretory (ES) molecules, which modulate the type... more Intestinal helminth parasites express excretory/secretory (ES) molecules, which modulate the type-2 immune response including anti-inflammatory and tissue repair pathways. TGF-β mimic (TGM), an ES molecule secreted by Heligmosomoides polygyrus (Hp), binds TGF-β receptors yet lacks structural homology to TGF-β and exhibits distinct receptor interactions. We demonstrate TGM treatment enhanced wound healing and tissue regeneration in an in vivo wound biopsy model. TGM, in a 1.5% carboxymethylcellulose solution, was topically administered beneath a Tegaderm layer. Through histological analysis, increased restoration of normal tissue structure in the wound beds of TGM-treated mice was observed during mid- to late-stage wound healing. These observations included accelerated re-epithelialization and hair follicle regeneration, without increased scarring. Flow cytometric and gene expression analysis showed differential expansion of myeloid populations at different stages of wound healing. T...
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is highly contagious and presents a ... more Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is highly contagious and presents a significant public health issue. Current therapies used to treat coronavirus disease 2019 (COVID-19) include monoclonal antibody cocktail, convalescent plasma, antivirals, immunomodulators, and anticoagulants. The vaccines from Pfizer and Moderna have recently been authorized for emergency use, which are invaluable for the prevention of SARS-CoV-2 infection. However, their long-term side effects are not yet documented, and populations with immunocompromised conditions (e.g., organ-transplantation and immunodeficient patients) may not be able to mount an effective immune response. In addition, there are concerns that wide-scale immunity to SARS-CoV-2 may introduce immune pressure that could select for escape mutants to the existing vaccines and monoclonal antibody therapies. Emerging evidence has shown that chimeric antigen receptor (CAR)- natural killer (NK) immunotherapy has potent anti...
or their / littermates were treated with a long-lasting formulation of recombinant mouse IL-4 (IL... more or their / littermates were treated with a long-lasting formulation of recombinant mouse IL-4 (IL-4C) or with IL-13 for seven days. Segments of jejunum were mounted in Ussing chambers to measure mucosal permeability; chloride secretion in response to PGE2, histamine, 5-hydroxytryptamine, or acetylcholine; and Na -linked glucose absorption. IL-4C and IL-13 increased mucosal permeability, decreased glucose absorption, and decreased chloride secretion in response to 5-hydroxytryptamine. These effects were dependent on STAT6 signaling. Responses to PGE2 and histamine, which were dependent on mast cells and STAT6, were enhanced by IL-4C, but not by IL-13. The effects of IL-4 and IL-13 on intestinal epithelial cell function may play a critical role in host protection against gastrointestinal nematodes. The Journal of Immunology, 2002, 169: 4417- 4422.
Laser capture microdissection (LCM) uses an infrared laser, incorporated within a standard micros... more Laser capture microdissection (LCM) uses an infrared laser, incorporated within a standard microscope, to isolate specific cells or tissues from samples mounted on microscope slides. The samples are viewed through a thermoplastic film that is attached to a microcentrifuge ...
We agree entirely with Hamilton and Stevens [1]. Our analyses in Thompson et al. [2] and Averis e... more We agree entirely with Hamilton and Stevens [1]. Our analyses in Thompson et al. [2] and Averis et al. [3] were designed to indicate the diversity of trypanosomes infecting Australian wildlife, rather than postulate any robust hypotheses of phylogeny. Although there was some evidence from our data of a close relationship between Trypanosoma lewisi and certain trypanosome genotypes from Australian native mammals, there is certainly a need for much more comprehensive analyses, using a wider range of loci and a broader range of trypanosome taxa. This is important for better understanding the biodiversity and ecology of trypanosome infections in Australian wildlife and the potential impact they might have on threatened populations [2,4].
Although primary and memory responses against bacteria and viruses have been studied extensively,... more Although primary and memory responses against bacteria and viruses have been studied extensively, T helper type 2 (T H 2) effector mechanisms leading to host protection against helminthic parasites remain elusive 1. Examination of the intestinal epithelial submucosa of mice after primary and secondary infections by a natural gastrointestinal parasite revealed a distinct immune-cell infiltrate after challenge, featuring interleukin-4-expressing memory CD4 + T cells that induced IL-4 receptor hi (IL-4R hi) CD206 + alternatively activated macrophages 2. In turn, these alternatively activated macrophages (AAMacs) functioned as important effector cells of the protective memory response contributing to parasite elimination, demonstrating a previously unknown mechanism for host protection against intestinal helminths. Productive adaptive immune responses result in CD4 + T-cell polarization into effector phenotypes defined by differing cytokine milieus 3. Helminth parasites and allergens induce T H 2 responses, including CD4 + T-cell interleukin (IL)-4 production promoting arginase-1 expression by alternatively activated macrophages (AAMacs) 4. Although it is known that these AAMacs accumulate during asthmatic inflammation 5 and helminth parasite infections 2,4,6, 7 , and downregulate type 1 inflammation 2,4,6 , a protective role for them remains undefined. Infection of mice with the natural mouse gastrointestinal helminth parasite Heligmosomoides polygyrus triggers a highly polarized T H 2 response 1. H. polygyrus infection is chronic with established adult worms; if parasites are cleared from the host's intestinal lumen, a rapid, protective T H 2 memory response operates against challenge infections 8. Our studies examined early events in this memory response to H. polygyrus larvae developing in the intestinal submucosa and indicated that AAMacs have an important role in parasite expulsion.
Helminth infections are ubiquitous worldwide and can trigger potent immune responses that differ ... more Helminth infections are ubiquitous worldwide and can trigger potent immune responses that differ from and potentially antagonize host protective responses to microbial pathogens. In this Review we focus on the three main killers in infectious disease-AIDS, tuberculosis and malaria-and critically assesses whether helminths adversely influence host control of these diseases. We also discuss emerging concepts for how M2 macrophages and helminth-modulated dendritic cells can potentially influence the protective immune response to concurrent infections. Finally, we present evidence advocating for more efforts to determine how and to what extent helminths interfere with the successful control of specific concurrent coinfections. Parasitic worms, or helminths, have probably coevolved with their vertebrate hosts for hundreds of millions of years. There is also abundant archaeological evidence that helminths have chronically infected humans, including the 5,000-year-old Neolithic 'Tyrolean Iceman', who was infected with the whipworm Trichuris trichiura 1. Ample evidence now indicates that helminths compromise fitness in wild vertebrate populations 2,3. In humans, although helminth infections are rarely lethal, they can contribute to morbidity in adults and impair physical and cognitive development in children 4,5. Generally, although the number of people infected by helminths in certain populations may be high, the frequency of people with high worm counts is usually low 6. That binomial distribution may be an important factor in considering the effects of helminths on the immune response to coinfecting microbes. Helminths are handled very differently by the host immune system than are microorganisms, such as fungi, protozoa, bacteria and viruses. Helminths include many very different multicellular worms that can reside mainly in tissues, such as filaria or schistosomes, or (alternatively) in the intestinal lumen, such as hookworms or Ascaris species. Generally, in both humans and mice, the characteristic helminth-induced type 2 immune response Reprints and permissions information
Urban, JF, Madden, KB, Svetica, A., Cheever, A., Trotta, PP, Gause, WC, Katona, IM and Finkelman,... more Urban, JF, Madden, KB, Svetica, A., Cheever, A., Trotta, PP, Gause, WC, Katona, IM and Finkelman, FD (1992), The Importance of Th2 Cytokines in Protective Immunity to Nematodes. Immunological Reviews, 127: 205220. doi: 10.1111/j. 1600-065X. 1992. ...
Summary: Components of the type 2 immune response may mediate host protection against both helmi... more Summary: Components of the type 2 immune response may mediate host protection against both helminthic parasites and harmful allergic responses. A central player in this response is the T‐helper 2 (Th2) effector cell, which produces interleukin (IL)‐4, IL‐5, IL‐13, and other Th2 cytokines during the primary and memory response. Specific aspects of the parasite that trigger Th2‐cell differentiation are not yet defined. Furthermore, the cell types and cell surface and secreted molecules that provide the immune milieu required for the development of Th2 effector cells and also Th2 memory cells are not well understood. They will probably vary with the particular helminth or other antigen inducing the Th2 response. We have used third stage larvae of intestinal nematode parasites as adjuvants to promote naïve nonparasite antigen‐specific T cells to differentiate into Th2 cells. This model system avoids possible parasite antigen‐specific T‐cell clones or cross‐reactive memory T cells that ...
Previous studies from our laboratory have shown an important role for B cells in the development ... more Previous studies from our laboratory have shown an important role for B cells in the development of Ag‐specific Th2 cells during a polarized Th2‐type response. In this study we examined the role of B cell in host protection to a nematode parasite, Heligmosomoides polygyrus (Hp). Hp is characterized by chronic infection following primary inoculation, but following drug‐induced worm clearance, secondary inoculation triggers a host protective memory Th2‐type response resulting in worm clearance. B cell deficient JhD and control WT mice were orally inoculated with Hp, followed by anti‐helminthic drug treatment on day 14, and one month later challenged with Hp. Compared to WT mice, JhD mice were much more susceptible to Hp infection with high numbers of worms. B cell deficiency did not affect T cell activation, IL‐4 and IL‐13 production by CD4 T cells in mesenteric lymph nodes, and alternatively activated macrophage activation in granulomas surrounding developing larvae in the submucosa....
Despite the promising clinical benefit of targeted and immune checkpoint blocking therapeutics, c... more Despite the promising clinical benefit of targeted and immune checkpoint blocking therapeutics, current strategies have limited success in breast cancer, indicating that additional inhibitory pathways are required to complement existing therapeutics. TAM receptors (Tyro-3, Axl, and Mertk) are often correlated with poor prognosis because of their capacities to sustain an immunosuppressive environment. Here, we ablate Axl on tumor cells using CRISPR/Cas9 gene editing, and by targeting Mertk in the tumor microenvironment (TME), we observed distinct functions of TAM as oncogenic kinases, as well as inhibitory immune receptors. Depletion of Axl suppressed cell intrinsic oncogenic properties, decreased tumor growth, reduced the incidence of lung metastasis and increased overall survival of mice when injected into mammary fat pad of syngeneic mice, and demonstrated synergy when combined with anti-PD-1 therapy. Blockade of Mertk function on macrophages decreased efferocytosis, altered the c...
More than 2 billion people worldwide are infected with helminths. Thus, it is possible for indivi... more More than 2 billion people worldwide are infected with helminths. Thus, it is possible for individuals to experience concomitant infection with helminth and intracellular microbes. Although the helminth-induced type 2 response can suppress type 1 proinflammatory responses required for the immunity against intracellular pathogens in the context of a coinfection, conflicting evidence suggest that helminth infection can enhance antimicrobial immunity. Using a coinfection model with the intestinal helminth Heligmosomoides polygyrus followed by infection with Toxoplasma gondii in Mus Musculus, we showed that the complex and dynamic effect of helminth infection is highly suppressive during the innate phase (days 0–3) of T. gondii infection and less stringent during the acute phase (d10). Helminth coinfection had a strong suppressive effect on the neutrophil, monocytic, and early IFN-γ/IL-12 responses. The IFN-γ response was later restored by compensatory production from T cells despite de...
CD4+ T cells are able to respond to various pathogens by differentiating into highly polarized T ... more CD4+ T cells are able to respond to various pathogens by differentiating into highly polarized T helper effector (Th) cells that regulate distinct immune responses. Bacteria and viruses can elicit a Th1 response and most helminth parasites can induce a Th2 response. Although, dendritic cells (DCs) are the most potent activators of naïve T cells in vitro, it remains unclear which cell population is most important under in vivo conditions to cause the polarization into effector groups. Naïve CD4+ T cells reside in T cell areas of secondary lymphoid organs and DC’s are the predominant MHC-II expressing cells in the T cell areas. To examine in vivo what antigen presenting cells (APCs) and accessory cells are associated with early stages of the Th2 response C57BL/6 mice received a subcutaneous ear injection in the context of an infectious helminth infection or Th1 inducing agent either in the presence or absence of Ealpha peptide. Local draining lymph nodes were harvested and flow cyto...
Regions of the world with high incidence of Tuberculosis (TB) are also endemic for helminthic dis... more Regions of the world with high incidence of Tuberculosis (TB) are also endemic for helminthic diseases. Helminthic infection elicits a profound Th2 immune response, which may alter theTh1 response necessary for the protection to TB. The impactof Th2 responses on the protective immune response elicited to TB is poorly understood. We co-infected BALB/c mice with the nematode Nippostrongylus brasiliensis (Nb) followed by virulent Erdman strain of Mtb via aerosolization. At 4 and 7 weeks post-Mtb infection, co-infected mice displayed significantly higher bacterial burden compared to mice infected with Mtb alone. Furthermore, the enhanced disease progression was accompanied by a shift in the Mtb-induced Th1 response to a Th2 response in the co-infected mice as demonstrated by an increase in Th2 cytokines IL-4 and IL-10. Taken together, theseresults demonstrate that helminth infection alters the ability of the host to mount an effective immune response to TB and modulates the course of tu...
Previous studies have suggested that resistin-like molecule beta (RELM-beta) contributes to prote... more Previous studies have suggested that resistin-like molecule beta (RELM-beta) contributes to protective immunity against intestinal nematode parasites by directly interfering with adult worm feeding in the lumen. Other studies have suggested that RELM-beta may also function in the mucosal milieu by regulating Th1/Th2 cytokine production. In our studies, we examined the development of the memory Th2-type response to the murine intestinal nematode parasite, Heligmosomoides polygyrus (Hp). Mice were inoculated with Hp, drug-cleared at day 14, and several weeks later given an Hp secondary inoculation. Consistent with previous studies, adult worm burden was increased in Hp inoculated RELM-beta KO compared to inoculated WT controls. Analysis of cytokine gene (RT-PCR) and protein (ELISPOT) expression in draining mesenteric lymph nodes (MLNs) showed reductions in Th2 cytokine levels in RELM-beta KO compared to WT mice at day 7 after Hp secondary inoculation. At this time point spleen weight ...
Intestinal helminth parasites express excretory/secretory (ES) molecules, which modulate the type... more Intestinal helminth parasites express excretory/secretory (ES) molecules, which modulate the type-2 immune response including anti-inflammatory and tissue repair pathways. TGF-β mimic (TGM), an ES molecule secreted by Heligmosomoides polygyrus (Hp), binds TGF-β receptors yet lacks structural homology to TGF-β and exhibits distinct receptor interactions. We demonstrate TGM treatment enhanced wound healing and tissue regeneration in an in vivo wound biopsy model. TGM, in a 1.5% carboxymethylcellulose solution, was topically administered beneath a Tegaderm layer. Through histological analysis, increased restoration of normal tissue structure in the wound beds of TGM-treated mice was observed during mid- to late-stage wound healing. These observations included accelerated re-epithelialization and hair follicle regeneration, without increased scarring. Flow cytometric and gene expression analysis showed differential expansion of myeloid populations at different stages of wound healing. T...
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is highly contagious and presents a ... more Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is highly contagious and presents a significant public health issue. Current therapies used to treat coronavirus disease 2019 (COVID-19) include monoclonal antibody cocktail, convalescent plasma, antivirals, immunomodulators, and anticoagulants. The vaccines from Pfizer and Moderna have recently been authorized for emergency use, which are invaluable for the prevention of SARS-CoV-2 infection. However, their long-term side effects are not yet documented, and populations with immunocompromised conditions (e.g., organ-transplantation and immunodeficient patients) may not be able to mount an effective immune response. In addition, there are concerns that wide-scale immunity to SARS-CoV-2 may introduce immune pressure that could select for escape mutants to the existing vaccines and monoclonal antibody therapies. Emerging evidence has shown that chimeric antigen receptor (CAR)- natural killer (NK) immunotherapy has potent anti...
or their / littermates were treated with a long-lasting formulation of recombinant mouse IL-4 (IL... more or their / littermates were treated with a long-lasting formulation of recombinant mouse IL-4 (IL-4C) or with IL-13 for seven days. Segments of jejunum were mounted in Ussing chambers to measure mucosal permeability; chloride secretion in response to PGE2, histamine, 5-hydroxytryptamine, or acetylcholine; and Na -linked glucose absorption. IL-4C and IL-13 increased mucosal permeability, decreased glucose absorption, and decreased chloride secretion in response to 5-hydroxytryptamine. These effects were dependent on STAT6 signaling. Responses to PGE2 and histamine, which were dependent on mast cells and STAT6, were enhanced by IL-4C, but not by IL-13. The effects of IL-4 and IL-13 on intestinal epithelial cell function may play a critical role in host protection against gastrointestinal nematodes. The Journal of Immunology, 2002, 169: 4417- 4422.
Laser capture microdissection (LCM) uses an infrared laser, incorporated within a standard micros... more Laser capture microdissection (LCM) uses an infrared laser, incorporated within a standard microscope, to isolate specific cells or tissues from samples mounted on microscope slides. The samples are viewed through a thermoplastic film that is attached to a microcentrifuge ...
We agree entirely with Hamilton and Stevens [1]. Our analyses in Thompson et al. [2] and Averis e... more We agree entirely with Hamilton and Stevens [1]. Our analyses in Thompson et al. [2] and Averis et al. [3] were designed to indicate the diversity of trypanosomes infecting Australian wildlife, rather than postulate any robust hypotheses of phylogeny. Although there was some evidence from our data of a close relationship between Trypanosoma lewisi and certain trypanosome genotypes from Australian native mammals, there is certainly a need for much more comprehensive analyses, using a wider range of loci and a broader range of trypanosome taxa. This is important for better understanding the biodiversity and ecology of trypanosome infections in Australian wildlife and the potential impact they might have on threatened populations [2,4].
Although primary and memory responses against bacteria and viruses have been studied extensively,... more Although primary and memory responses against bacteria and viruses have been studied extensively, T helper type 2 (T H 2) effector mechanisms leading to host protection against helminthic parasites remain elusive 1. Examination of the intestinal epithelial submucosa of mice after primary and secondary infections by a natural gastrointestinal parasite revealed a distinct immune-cell infiltrate after challenge, featuring interleukin-4-expressing memory CD4 + T cells that induced IL-4 receptor hi (IL-4R hi) CD206 + alternatively activated macrophages 2. In turn, these alternatively activated macrophages (AAMacs) functioned as important effector cells of the protective memory response contributing to parasite elimination, demonstrating a previously unknown mechanism for host protection against intestinal helminths. Productive adaptive immune responses result in CD4 + T-cell polarization into effector phenotypes defined by differing cytokine milieus 3. Helminth parasites and allergens induce T H 2 responses, including CD4 + T-cell interleukin (IL)-4 production promoting arginase-1 expression by alternatively activated macrophages (AAMacs) 4. Although it is known that these AAMacs accumulate during asthmatic inflammation 5 and helminth parasite infections 2,4,6, 7 , and downregulate type 1 inflammation 2,4,6 , a protective role for them remains undefined. Infection of mice with the natural mouse gastrointestinal helminth parasite Heligmosomoides polygyrus triggers a highly polarized T H 2 response 1. H. polygyrus infection is chronic with established adult worms; if parasites are cleared from the host's intestinal lumen, a rapid, protective T H 2 memory response operates against challenge infections 8. Our studies examined early events in this memory response to H. polygyrus larvae developing in the intestinal submucosa and indicated that AAMacs have an important role in parasite expulsion.
Helminth infections are ubiquitous worldwide and can trigger potent immune responses that differ ... more Helminth infections are ubiquitous worldwide and can trigger potent immune responses that differ from and potentially antagonize host protective responses to microbial pathogens. In this Review we focus on the three main killers in infectious disease-AIDS, tuberculosis and malaria-and critically assesses whether helminths adversely influence host control of these diseases. We also discuss emerging concepts for how M2 macrophages and helminth-modulated dendritic cells can potentially influence the protective immune response to concurrent infections. Finally, we present evidence advocating for more efforts to determine how and to what extent helminths interfere with the successful control of specific concurrent coinfections. Parasitic worms, or helminths, have probably coevolved with their vertebrate hosts for hundreds of millions of years. There is also abundant archaeological evidence that helminths have chronically infected humans, including the 5,000-year-old Neolithic 'Tyrolean Iceman', who was infected with the whipworm Trichuris trichiura 1. Ample evidence now indicates that helminths compromise fitness in wild vertebrate populations 2,3. In humans, although helminth infections are rarely lethal, they can contribute to morbidity in adults and impair physical and cognitive development in children 4,5. Generally, although the number of people infected by helminths in certain populations may be high, the frequency of people with high worm counts is usually low 6. That binomial distribution may be an important factor in considering the effects of helminths on the immune response to coinfecting microbes. Helminths are handled very differently by the host immune system than are microorganisms, such as fungi, protozoa, bacteria and viruses. Helminths include many very different multicellular worms that can reside mainly in tissues, such as filaria or schistosomes, or (alternatively) in the intestinal lumen, such as hookworms or Ascaris species. Generally, in both humans and mice, the characteristic helminth-induced type 2 immune response Reprints and permissions information
Urban, JF, Madden, KB, Svetica, A., Cheever, A., Trotta, PP, Gause, WC, Katona, IM and Finkelman,... more Urban, JF, Madden, KB, Svetica, A., Cheever, A., Trotta, PP, Gause, WC, Katona, IM and Finkelman, FD (1992), The Importance of Th2 Cytokines in Protective Immunity to Nematodes. Immunological Reviews, 127: 205220. doi: 10.1111/j. 1600-065X. 1992. ...
Summary: Components of the type 2 immune response may mediate host protection against both helmi... more Summary: Components of the type 2 immune response may mediate host protection against both helminthic parasites and harmful allergic responses. A central player in this response is the T‐helper 2 (Th2) effector cell, which produces interleukin (IL)‐4, IL‐5, IL‐13, and other Th2 cytokines during the primary and memory response. Specific aspects of the parasite that trigger Th2‐cell differentiation are not yet defined. Furthermore, the cell types and cell surface and secreted molecules that provide the immune milieu required for the development of Th2 effector cells and also Th2 memory cells are not well understood. They will probably vary with the particular helminth or other antigen inducing the Th2 response. We have used third stage larvae of intestinal nematode parasites as adjuvants to promote naïve nonparasite antigen‐specific T cells to differentiate into Th2 cells. This model system avoids possible parasite antigen‐specific T‐cell clones or cross‐reactive memory T cells that ...
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Papers by William Gause