Biomedical subjects

C Maliszewski

Publications and source records attributed to C Maliszewski.

At least 19 recordsLinked to original sources

PubMed2004

Differential capacity of CD8+ alpha or CD8- alpha dendritic cell subsets to prime for eosinophilic airway inflammation in the T-helper type 2-prone milieu of the lung.

BACKGROUND: Different subsets of dendritic cells (DCs), identified in mouse spleen by their differential expression of CD8 alpha, can induce different T-helper (Th) responses after systemic administration. CD8 alpha(-) DCs have been shown to preferentially induce Th type 2 (Th2) responses whereas CD8 alpha(+) DCs induce Th1 responses. OBJECTIVE: To study if these DC subsets can still induce different Th responses in the Th2-prone milieu of the lung and differentially prime for eosinophilic airway inflammation, typical of asthma. METHODS: Donor mice first received daily Flt3L injections to expand DC numbers. Purified CD8 alpha(+) or CD8 alpha(-) splenic DCs were pulsed with ovalbumin (OVA) or phosphate-buffered saline and injected intratracheally into recipient mice in which carboxyfluorescein diacetate succinimidyl ester-labelled OVA-specific T cell receptor transgenic T cells had been injected intravenously 2 days earlier. T cell proliferation and cytokine production of Ag-specific T cells were evaluated in the mediastinal lymph nodes (MLNs) 4 days later. The capacity of both subsets of DCs, to prime for eosinophilic airway inflammation was determined by challenging the mice with OVA aerosol 10 days later. RESULTS: CD8 alpha(-) DCs migrated to the MLN and induced a vigorous proliferative T cell response accompanied by high-level production of IL-4, IL-5, IL-10 and also IFN-gamma during the primary response and during challenge with aerosol, leading to eosinophilic airway inflammation. In the absence of migration to the MLN, CD8 alpha(+) DCs still induced a proliferative response with identical levels of IFN-gamma but reduced Th2 cytokines compared with CD8 alpha(-) DCs, which led to weak eosinophilic airway inflammation upon OVA aerosol challenge. Unpulsed DCs did not induce proliferation or cytokine production in Ag-specific T cells. CONCLUSION: CD8 alpha(-) DCs are superior compared with CD8 alpha(+) DCs in inducing Th2 responses and eosinophilic airway inflammation in the Th2-prone environment of the lung.

Animals↗

PubMed2001

Cytokines regulate the capacity of CD8alpha(+) and CD8alpha(-) dendritic cells to prime Th1/Th2 cells in vivo.

Prior studies have shown that subclasses of dendritic cells (DC) direct the development of distinct Th populations in rodents and in humans. In the mouse, we have recently shown that administration of Ag-pulsed CD8alpha(-) DC induces a Th2-type response, whereas injection of CD8alpha(+) DC leads to Th1 differentiation. To define the DC-derived factors involved in the polarization of Th responses, we injected either subset purified from mice genetically deficient for IFN-gamma, IL-4, IL-12, or IL-10 into wild-type animals. In this work, we report that DC-derived IL-12 and IFN-gamma are required for Th1 priming by CD8alpha(+) DC, whereas IL-10 is required for optimal development of Th2 cells by CD8alpha(-) DC. The level of IL-12 produced by the DC appears to determine the Th1/Th2 balance in vivo. We further show that the function of DC subsets displays some flexibility. Treatment of DC with IL-10 in vitro induces a selective decrease in the viability of CD8alpha(+) DC. Conversely, incubation with IFN-gamma down-regulates the Th2-promoting capacities of CD8alpha(-) DC and increases the Th1-skewing properties of both subsets.

Animals↗

PubMed2001

Bidirectional negative regulation of human T and dendritic cells by CD47 and its cognate receptor signal-regulator protein-alpha: down-regulation of IL-12 responsiveness and inhibition of dendritic cell activation.

Proinflammatory molecules, including IFN-gamma and IL-12, play a crucial role in the elimination of causative agents. To allow healing, potent anti-inflammatory processes are required to down-regulate the inflammatory response. In this study, we first show that CD47/integrin-associated protein, a ubiquitous multispan transmembrane protein highly expressed on T cells, interacts with signal-regulator protein (SIRP)-alpha, an immunoreceptor tyrosine-based inhibition motif-containing molecule selectively expressed on myelomonocytic cells, and next demonstrate that this pair of molecules negatively regulates human T and dendritic cell (DC) function. CD47 ligation by CD47 mAb or L-SIRP-alpha transfectants inhibits IL-12R expression and down-regulates IL-12 responsiveness of activated CD4(+) and CD8(+) adult T cells without affecting their response to IL-2. Human CD47-Fc fusion protein binds SIRP-alpha expressed on immature DC and mature DC. SIRP-alpha engagement by CD47-Fc prevents the phenotypic and functional maturation of immature DC and still inhibits cytokine production by mature DC. Finally, in allogeneic MLR between mDC and naive T cells, CD47-Fc decreases IFN-gamma production after priming and impairs the development of a Th1 response. Therefore, CD47 on T cells and its cognate receptor SIRP-alpha on DC define a novel regulatory pathway that may be involved in the maintenance of homeostasis by preventing the escalation of the inflammatory immune response.

Antibodies, Monoclonal↗

PubMed2001

Dendritic cells recruitment and in vivo priming of CD8+ CTL induced by a single topical or transepithelial immunization via the buccal mucosa with measles virus nucleoprotein.

The buccal mucosa, a prototype of pluristratified mucosal epithelia, contains a network of directly accessible class II(+) epithelial dendritic cells (DC), similar to skin Langerhans cells. We showed that a single buccal immunization with measles virus nucleoprotein (NP), by either topical application onto or intradermal injection in the buccal mucosa, induced in vivo priming of protective class I-restricted specific CD8(+) CTL. Both routes of immunization with NP induced a rapid recruitment of DC into the mucosa, which peaked at 2 h and decreased by 24 h. Treatment of mice with Flt3 ligand resulted in an increased number of DC in the buccal mucosa and enhanced the frequency of IFN-gamma-producing NP-specific effectors and the NP-specific CTL response generated after buccal immunization with NP. Finally, NP-pulsed bone marrow-derived DC induced NP-specific IFN-gamma-producing cells upon adoptive transfer to naive mice. These data demonstrate that a viral protein delivered to DC of the buccal mucosa induces in vivo priming of protective anti-viral CD8(+) CTL.

Adjuvants, Immunologic↗

PubMed2001

Dendritic cell longevity and T cell persistence is controlled by CD154-CD40 interactions.

Inflammatory mediators facilitate the maturation of dendritic cells (DC), enabling them to induce the activation, proliferation and differentiation of cognate T cells. The role of CD40 on DC and CD154 on T cells has been studied by the co-adoptive transfer of antigen-pulsed DC and TCR-transgenic (Tg) T cells in vivo. It is shown that in the absence of CD40-CD154 interactions, initial Tg T cell expansion occurs in vivo, but over time, T cell expansion cannot be sustained. The basis for the demise of the T cell population is likely due to the disappearance of the antigen-pulsed DC in the draining lymph nodes when CD154-CD40 interactions are interrupted. These findings show that both T cell and DC persistence in vivo is dependent on CD40-CD154 interactions. In addition to the physical persistence of the DC, CD40 triggering of DC also greatly increases the period for which they can productively present antigen to Tg T cells. Hence DC persistence and antigen-presenting cell capacity are both dependent on CD40 signaling. While TNF-alpha can mature DC as measured by a variety of criteria, the unique capacity of CD40 signaling to sustain T cell responses and induce DC maturation is underscored by the inability of TNF-alpha to rescue the immune deficiency of CD40(-/-) DC. Hence, the profound impact of CD154 deficiency on cell-mediated immunity may be due to its ability to limit the duration of antigen presentation in vivo and cause the premature demise of antigen-specific T cells.

Adoptive Transfer↗

PubMed2001

Dendritic cells in models of tumor immunity. Role of Flt3 ligand.

Cancer immunotherapy might be based on the administration to cancer patients of dendritic cells (DC) 'pulsed' with tumor-specific antigens. An alternative approach is to directly expand and/or activate DC in vivo using the cytokine Flt3 Ligand (FL). In mice, FL can drive large expansion of both lymphoid-related DC that appears to selectively enhance Th1-like immune responses and myeloid-related DC that enhances a more mixed Th phenotype. Immunization of FL-treated mice with a protein antigen leads to increased production of antibodies specific for that protein as well as to antigen-specific helper T cell responses. Studies of mouse tumor models have demonstrated that FL administration leads to the generation of protective anti-tumor immune responses, these effects being mediated by CTL and/or NK cells. When, FL has only minor or short term effects, the anti-tumor response can be significantly amplified by adding other cytokines, known to act at the T cell level, such as CD40 ligand (CD40L) or 4-1BBL, a TNF family member. Thus, combination of FL + CD40L or FL + 4-1BBL have superior anti-tumor effects vs. either cytokine alone. In conclusion, cytokines offer a variety of novel approaches for the treatment of cancer, infectious or auto-immune diseases.

Adjuvants, Immunologic↗

PubMed2001

Modulating the immune response with dendritic cells and their growth factors.

Different subsets of dendritic cells (DCs) appear to play a role in determining the specific cytokines secreted by T helper (Th) cells. A model is proposed that links together factors such as the pathogen, microenvironment, DCs and T cells in a mechanism that results in a flexible determination of T-cell polarization.

Adjuvants, Immunologic↗

PubMed2001

Induction of polyomavirus-specific CD8(+) T lymphocytes by distinct dendritic cell subpopulations.

Dendritic cells are pivotal antigen-presenting cells for generating adaptive T-cell responses. Here, we show that dendritic cells belonging to either the myeloid-related or lymphoid-related subset are permissive for infection by mouse polyomavirus and, when loaded with a peptide corresponding to the immunodominant anti-polyomavirus CD8(+) T-cell epitope or infected by polyomavirus, are each capable of driving expansion of primary polyomavirus-specific CD8(+) T-cell responses in vivo.

Animals↗

PubMed2001

Thromboregulation by endothelial cells: significance for occlusive vascular diseases.

-During their 7- to 9-day lifespan in the circulation, platelets perform an ill-defined baseline function that maintains the integrity of the vasculature. In thrombocytopenic states, there is an increase in vascular permeability and fragility, which is presumably due to absence of this platelet function. In sharp contrast, biochemical or physical injury in the coronary, carotid, or peripheral arteries induces platelet activation and platelet recruitment, which can progress to thrombotic vascular occlusion. Because there is 1 death every 33 seconds from vascular occlusion in the United States, this problem has critical public health implications. In this review, we describe the characterization of a novel potential antithrombotic agent with a unique mode of action-biochemical "deletion" of ADP from an activated platelet releasate, which thereby inhibits platelet recruitment and further activation.

Arterial Occlusive Diseases↗

PubMed2001

CD8alpha(-) and CD8alpha(+) subclasses of dendritic cells undergo phenotypic and functional maturation in vitro and in vivo.

Dendritic cells (DCs) are essential for the priming of immune responses. This antigen-presenting function of DCs develops in sequence in a process called maturation, during which they become potent sensitizers of naïve T cells but reduce their ability to capture and process antigens. Some heterogeneity exists in mouse-DC populations, and two distinct subsets of DCs expressing high levels of CD11c can be identified on the basis of CD8alpha expression. We have studied the phenotype and maturation state of mouse splenic CD8alpha(-) and CD8alpha(+) DCs. Both subsets were found to reside in the spleen as immature cells and to undergo a phenotypic maturation upon culture in vitro in GM-CSF-containing medium or in vivo in response to lipopolysaccharide. In vitro and in vivo analyses showed that this maturation process is an absolute requisite for DCs to acquire their T-cell priming capacity, transforming CD8alpha(-) and CD8alpha(+) DCs into potent and equally efficient activators of naïve CD4(+) and CD8(+) T cells. Furthermore, these results highlight the importance that environmental factors may have on the ability of DC subsets to influence Th responses qualitatively; i.e., the ability to drive Th1 versus Th2 differentiation may not be fixed immutably for each DC subset.

Adoptive Transfer↗

PubMed2000

Peroxisome proliferator-activated receptor gamma activators inhibit interleukin-12 production in murine dendritic cells.

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily. They are divided into three subtypes (alpha, beta or delta, and gamma) and are involved in lipid and glucose homeostasis and in the control of inflammation. In this study, we analyzed the expression of PPARs in murine dendritic cells (DCs), the most potent antigen presenting cells. We find that immature as well as mature spleen-derived DCs express PPARgamma, but not PPARalpha, mRNA and protein. We also show that the PPARgamma activator rosiglitazone does not interfere with the maturation of DCs in vitro nor modifies their ability to activate naive T lymphocytes in vivo. Finally, we present evidence that PPARgamma activators down-modulate the CD40-induced secretion of interleukin-12, a potent Th1-driving factor. These data suggest a possible role for PPARgamma in the regulation of immune responses.

Animals↗

PubMed2000

B lymphocytes regulate dendritic cell (DC) function in vivo: increased interleukin 12 production by DCs from B cell-deficient mice results in T helper cell type 1 deviation.

Increasing evidence indicates that dendritic cells (DCs) are the antigen-presenting cells of the primary immune response. However, several reports suggest that B lymphocytes could be required for optimal T cell sensitization. We compared the immune responses of wild-type and B cell-deficient (muMT) mice, induced by antigen emulsified in adjuvant or pulsed on splenic dendritic cells. Our data show that lymph node cells from both control and muMT animals were primed, but each released distinct cytokine profiles. Lymph node T cells from control animals secreted interferon (IFN)-gamma, interleukin (IL)-2, and IL-4, whereas those from muMT mice produced IFN-gamma and IL-2 but no IL-4. To test whether B cells may influence the T helper cell type 1 (Th1)/Th2 balance by affecting the function of DCs, we immunized mice by transferring antigen-pulsed DCs from wild-type or mutant mice. Injection of control DCs induced the secretion of IL-4, IFN-gamma, and IL-2, whereas administration of DCs from muMT animals failed to sensitize cells to produce IL-4. Analysis of IL-12 production revealed that DCs from muMT mice produce higher levels of IL-12p70 than do DCs from wild-type animals. These data suggest that B lymphocytes regulate the capacity of DCs to promote IL-4 secretion, possibly by downregulating their secretion of IL-12, thereby favoring the induction of a nonpolarized immune response.

Adjuvants, Immunologic↗

PubMed2000

Flt3-ligand and granulocyte colony-stimulating factor mobilize distinct human dendritic cell subsets in vivo.

Dendritic cells (DCs) have a unique ability to stimulate naive T cells. Recent evidence suggests that distinct DC subsets direct different classes of immune responses in vitro and in vivo. In humans, the monocyte-derived CD11c+ DCs induce T cells to produce Th1 cytokines in vitro, whereas the CD11c- plasmacytoid T cell-derived DCs elicit the production of Th2 cytokines. In this paper we report that administration of either Flt3-ligand (FL) or G-CSF to healthy human volunteers dramatically increases distinct DC subsets, or DC precursors, in the blood. FL increases both the CD11c+ DC subset (48-fold) and the CD11c- IL-3R+ DC precursors (13-fold). In contrast, G-CSF only increases the CD11c- precursors (>7-fold). Freshly sorted CD11c+ but not CD11c- cells stimulate CD4+ T cells in an allogeneic MLR, whereas only the CD11c- cells can be induced to secrete high levels of IFN-alpha, in response to influenza virus. CD11c+ and CD11c- cells can mature in vitro with GM-CSF + TNF-alpha or with IL-3 + CD40 ligand, respectively. These two subsets up-regulate MHC class II costimulatory molecules as well as the DC maturation marker DC-lysosome-associated membrane protein, and they stimulate naive, allogeneic CD4+ T cells efficiently. These two DC subsets elicit distinct cytokine profiles in CD4+ T cells, with the CD11c- subset inducing higher levels of the Th2 cytokine IL-10. The differential mobilization of distinct DC subsets or DC precursors by in vivo administration of FL and G-CSF offers a novel strategy to manipulate immune responses in humans.

Adjuvants, Immunologic↗

PubMed2000

Polyomavirus-infected dendritic cells induce antiviral CD8(+) T lymphocytes.

CD8(+) T cells are critical for the clearance of acute polyomavirus infection and the prevention of polyomavirus-induced tumors, but the antigen-presenting cell(s) involved in generating polyomavirus-specific CD8(+) T cells have not been defined. We investigated whether dendritic cells and macrophages are permissive for polyomavirus infection and examined their potential for inducing antiviral CD8(+) T cells. Although dendritic cells and macrophages both supported productive polyomavirus infection, dendritic cells were markedly more efficient at presenting the immunodominant viral epitope to CD8(+) T cells. Additionally, infected dendritic cells, but not infected macrophages, primed anti-polyomavirus CD8(+) T cells in vivo. Treatment with Flt3 ligand, a hematopoietic growth factor that dramatically expands the number of dendritic cells, markedly enhanced the magnitude of virus-specific CD8(+) T-cell responses during acute infection and the pool of memory anti-polyomavirus CD8(+) T cells. These findings suggest that virus-infected dendritic cells induce polyomavirus-specific CD8(+) T cells in vivo and raise the potential for their use as cellular adjuvants to promote CD8(+) T cell surveillance against polyomavirus-induced tumors.

3T3 Cells↗

PubMed1999

The vitronectin receptor and its associated CD47 molecule mediates proinflammatory cytokine synthesis in human monocytes by interaction with soluble CD23.

The vitronectin receptor, alphavbeta3 integrin, plays an important role in tumor cell invasion, angiogenesis, and phagocytosis of apoptotic cells. CD47, a member of the multispan transmembrane receptor family, physically and functionally associates with vitronectin receptor (VnR). Although vitronectin (Vn) is not a ligand of CD47, anti-CD47 and beta3 mAbs suppress Vn, but not fibronectin (Fn) binding and function. Here, we show that anti-CD47, anti-beta3 mAb and Vn, but not Fn, inhibit sCD23-mediated proinflammatory function (TNF-alpha, IL-12, and IFN-gamma release). Surprisingly, anti-CD47 and beta3 mAbs do not block sCD23 binding to alphav+beta3+ T cell lines, whereas Vn and an alphav mAb (clone AMF7) do inhibit sCD23 binding, suggesting the VnR complex may be a functional receptor for sCD23. sCD23 directly binds alphav+beta3+/CD47(-) cell lines, but coexpression of CD47 increases binding. Moreover, sCD23 binds purified alphav protein and a single human alphav chain CHO transfectant. We conclude that the VnR and its associated CD47 molecule may function as a novel receptor for sCD23 to mediate its proinflammatory activity and, as such, may be involved in the inflammatory process of the immune response.

Animals↗

PubMed1999

Differential regulation of epidermal and dermal dendritic cells by IL-12 and Flt3 ligand.

An abrogation of the decline in epidermal Langerhans cell numbers above melanoma might significantly improve the efficacy of immunotherapy for melanoma treatment. Systemic Flt3 ligand (FL) administration in mice induced a significant increase in mature dendritic cells (DC) within the skin, preferentially in the dermis, whereas IL-12 promoted a significant increase of immature DC preferentially in the epidermis. Both effects were abrogated in IL-12 knockout mice. Thus, IL-12 could promote FL-induced accumulation of skin DC. The involvement of FL and IL-12 in the regulation of DC accumulation within the skin may contribute, at least in part, to the stimulation of antimelanoma immunity by FL- and IL-12-based immunotherapies. Moreover, FL and IL-12 could be used for selective in vivo generation of DC in either epidermis or dermis for experimental and clinical purposes.

Animals↗

PubMed1998

FLT3-ligand administration inhibits liver metastases: role of NK cells.

FLT3-ligand (FL) is a recently described cytokine that stimulates the proliferation and differentiation of hematopoietic progenitors both in vivo and in vitro and, when administered to mice, induces an accumulation of dendritic cells (DC) in different lymphoid and nonlymphoid organs and tissues, including the liver. We have studied the antitumor effect of FL administered alone or in combination with IL-12 in a day 3 murine liver metastasis model. FL significantly reduced the number of hepatic metastases (36.00 +/- 11.00 vs 92.00 +/- 10.19 in control group, p < 0.05). Histologic evaluation of the livers revealed that FL induced a significant infiltration of the tumor border by lymphocytes and DC associated with increased number of apoptotic figures. Immunohistochemical analysis demonstrated that FL significantly enhanced the number of DC in the liver parenchyma and within the liver metastases, as well as the number of CD4+ and CD8+ T lymphocytes. These data support the suggestion that DC may be directly involved in the antitumor effect of FL. Interestingly, the antitumor effect of FL was greatly reduced by the NK depletion. Combination of FL and IL-12 resulted in greater antitumor efficacy than these cytokines alone. In summary, we have shown that FL has significant antitumor effect on preexisting murine C3 liver tumors that is mediated by NK cells. We have also demonstrated that the FL/IL-12 combination has an enhanced antitumor activity in the same murine tumor model.

Adjuvants, Immunologic↗

PubMed1998

FLT3 ligand administration inhibits tumor growth in murine melanoma and lymphoma.

Successful treatment of melanoma and lymphoma may result from the induction of specific antitumor immunity. Dendritic cells (DCs) are powerful antigen-presenting cells and show a remarkable capacity to stimulate antigen-specific T-cell responses. Administration of FLT3 ligand (FL) results in a reversible accumulation of functionally active DCs in both lymphoid and nonlymphoid tissues. Therefore, we evaluated the possible antitumor effect of FL in murine melanoma (B16 and CL8-1) and lymphoma (EL-4) models. In all experiments, tumor growth was significantly inhibited by FL administration. Analysis by immunohistochemistry revealed an increase in the DC accumulation within B16 and EL-4 tumors after treatment with FL. No change was observed for CL8-1 melanoma. These data suggest a potential role for FL in the immunotherapy of malignant skin tumors and possible DC involvement in this effect.

Animals↗