Biomedical subjects

E Pearlman

Publications and source records attributed to E Pearlman.

At least 37 records · Page 2Linked to original sources

PubMed1998

Type 2 immune deviation has differential effects on alloreactive CD4+ and CD8+ T cells.

Allograft rejection has been associated with detection of the type 1 lymphokines, IFN-gamma and IL-2. The role of type 2 cytokines (IL-4 and IL-5) remains controversial, as is whether alloreactive CD4+ and CD8+ T cells behave similarly when exposed to type 2 cytokine-enhancing manipulations. We studied the characteristics of alloreactive CD4+ and CD8+ T cells before and after type 2 immune deviation induced by IL-4 plus anti-IFN-gamma Ab. Alloreactive T cells from naive mice were low in frequency, produced only IL-2, and were predominantly CD4+, while alloreactive T cells from allograft-primed mice were high in frequency, produced IFN-gamma, IL-2, and IL-4, and were predominantly CD8+. Type 2 immune deviation of allospecific CD4+ T cells resulted in IL-4 and IL-5 production without IFN-gamma, consistent with unipolar type 2 immunity. These T cells mediated delayed-type hypersensitivity, but not cytotoxicity. Under identical type 2 cytokine-inducing conditions, allospecific CD8+ T cells were primed to become IL-4, IL-5, and IFN-gamma producers, and exhibited cytotoxicity, but not classic delayed-type hypersensitivity. Adoptive transfer of either cell population into SCID recipients of allogeneic skin resulted in graft rejection, with stable allospecific type 2 cytokine production in vivo. Adoptive transfer of the IL-4/IL-5-producing CD4+ T cells, but not the CD8+ T cells, induced a distinct histopathology characterized by marked eosinophilic infiltration of the skin. We conclude that type 2 immune deviation has differential effects on CD4+ and CD8+ T cells and results in emergence of alternate effector mechanisms capable of destroying allografts.

Animals↗

PubMed1998

Eotaxin is required for the baseline level of tissue eosinophils.

Eotaxin is an eosinophil-selective chemokine that is constitutively expressed in a variety of organs such as the intestine. Previous studies have demonstrated that the recruitment of eosinophils during inflammation is partially dependent on eotaxin, but the function of constitutive eotaxin during homeostasis has not been examined. To elucidate the biological role of this molecule, we now examine tissue levels of eosinophils in healthy states in wild-type and eotaxin-deficient mice. The lamina propria of the jejunum of wild-type mice is demonstrated to express eotaxin mRNA, but not mRNA for the related monocyte chemoattractant proteins. Wild-type mice contained readily detectable eosinophils in the lamina propria of the jejunum. In contrast, mice genetically deficient in eotaxin had a large selective reduction in the number of eosinophils residing in the jejunum. The reduction of tissue eosinophils was not limited to the jejunum, because a loss of thymic eosinophils was also observed in eotaxin-deficient mice. These studies demonstrate that eotaxin is a fundamental regulator of the physiological trafficking of eosinophils during healthy states. Because a variety of chemokines are constitutively expressed, their involvement in the baseline trafficking of leukocytes into nonhematopoietic tissue should now be considered.

Animals↗

PubMed1998

Interleukin-12 suppresses filaria-induced pulmonary eosinophilia, deposition of major basic protein and airway hyperresponsiveness.

Tropical Pulmonary Eosinophilia (TPE) is a severe form of allergic asthma caused by the host inflammatory response to filarial helminths in the lung microvasculature, and is characterized by pulmonary eosinophilia, increased filarial-specific IgG and IgE antibodies, and airway hyperresponsiveness. The current study examined the effect of IL-12 on pulmonary eosinophilia, deposition of eosinophil major basic protein and airway hyperresponsiveness in mice inoculated i.v. with Brugia malayi microfilariae. Injection of recombinant murine IL-12 modulated the T helper (Th) response in the lungs from Th2- to Th1-like, with elevated IFN-gamma, and decreased IL-4 and IL-5 production. Consistent with this shift in cytokine response, antigen-specific IgG2a was elevated, and IgG1 and total serum IgE were decreased. In addition, eosinophils in BAL fluid from IL-12 treated mice were reduced from 56% to 11%, and there was no detectable MBP on respiratory epithelial cells. Importantly, IL-12 suppressed airway hyperresponsiveness compared with saline-injected control animals. Taken together, these data clearly demonstrate that by modulating Th associated cytokine production, IL-12 down-regulates filaria-induced lung immunopathology.

Animals↗

PubMed1998

Interleukin-12 and the host response to parasitic helminths; the paradoxical effect on protective immunity and immunopathology.

In general, helminth infections are associated with the development of dominant Th2-mediated immune responses which may be host protective but can also be the cause of immunopathology. Interleukin 12 (IL-12) is known to be a potent inhibitor of Th2 immune responses and as such it might be expected to have an important modulatory role in helminth-induced immune responses. In this review, we discuss the effect of IL-12 on susceptibility to infection, protective immunity and immunopathology, in the context of exposure to a range of helminths including intestinal nematodes, filariae and schistosomes. It is apparent that the effects of IL-12 are complex and can be beneficial as well as detrimental for the host. The precise role of IL-12 depends upon a number of factors including the type of helminth and the specific tissue involved in the inflammatory response.

Animals↗

PubMed1998

An essential role for interleukin-5 and eosinophils in helminth-induced airway hyperresponsiveness.

Infection with the parasitic helminth Brugia malayi can result in development of a severe asthmatic response termed tropical pulmonary eosinophilia. This disease, thought to result from a host inflammatory response to blood parasites which become trapped in the lung microvasculature, is characterized by a profound eosinophilic infiltration into the lungs. Recruitment of eosinophils also correlates with the development of airway hyperresponsiveness (AHR) to cholinergic agonists and severe asthmatic symptoms. Our studies examined the role of interleukin-5 (IL-5) in helminth-induced pulmonary eosinophilia and AHR. C57BL/6 mice immunized with killed B. malayi microfilariae and challenged intravenously with live microfilariae exhibit many of the characteristics of human disease, including peripheral and pulmonary eosinophilia. Cells recovered by bronchoalveolar lavage of sensitized mice consisted of 3.8% eosinophils on day 1 postchallenge and 84% on day 10. Extracellular major basic protein was present on the surface of airway epithelial cells as early as day 1 and continued to be evident after 8 days, indicating sustained activation and degranulation of eosinophils in the lung. These histologic changes correlated with the development of AHR to carbachol. In contrast to immunocompetent mice, immunization and challenge with B. malayi in IL-5(-/-) mice did not induce peripheral or pulmonary eosinophilia, and these mice failed to show AHR in response to cholinergic agonists. Taken together, these data indicate that IL-5 and eosinophils are required for the induction of AHR by filarial helminths.

Animals↗

PubMed1998

The role of eosinophils and neutrophils in helminth-induced keratitis.

PURPOSE: Intrastromal injection of mice with antigens from the parasitic helminth that causes river blindness (Onchocerca volvulus) induces eosinophil recruitment to the corneal stroma at the time of maximum corneal opacification and neovascularization. The present study was conducted to examine the role of eosinophils and neutrophils in onchocercal keratitis in control C57Bl/6 mice and in interleukin-5 gene knockout (IL-5(-/-)) mice. METHODS: C57Bl/6 and IL-5(-/-) mice were immunized subcutaneously and injected intrastromally with soluble O. volvulus antigens. Mice were killed at various times thereafter. Development of keratitis was assessed by slit lamp examination, and inflammatory cells in the cornea were identified by immunohistochemistry. RESULTS: A biphasic recruitment of inflammatory cells was observed in C57Bl/6 mice; neutrophils predominated during the first 72 hours after intrastromal injection and subsequently declined, whereas eosinophil recruitment increased as time elapsed and comprised the majority (90%) of cells in the cornea by day 7. In contrast, neutrophils were the predominant inflammatory cells in IL-5(-/-) mice at early and late time points and were associated with extensive stromal damage and corneal opacification and neovascularization. Eosinophils were not detected in these mice at any time. CONCLUSIONS: In the absence of eosinophils, neutrophils can mediate keratitis induced by helminth antigens. Together with the early neutrophilic infiltrate in control animals, these observations indicate that neutrophils have an important role in onchocercal keratitis.

Animals↗

PubMed1997

B7-2 requirement for helminth-induced granuloma formation and CD4 type 2 T helper cell cytokine expression.

B7 ligands on APCs engage CD28/CTLA4 counter-receptors on T cells critical for T lymphocyte activation and functional differentiation of T helper subsets. To examine whether the ligands B7-1 (CD80) and B7-2 (CD86) affect gene expression of Th2 cytokines and development of Th2-mediated pathologic tissue reactions, mice were treated with anti-B7-1 or anti-B7-2 at the time of sensitization to footpad inoculation of Schistosoma mansoni eggs or induction of pulmonary granuloma by i.v. injected eggs. Anti-B7-2 treatment inhibited pulmonary granuloma formation by 74% and decreased levels of lung IL-5 and IL-13 transcripts compared with those in animals given control Ig by 20- and 5-fold, respectively, while anti-B7-1 administration has no effect. Anti-B7-2 treatment blocked CD4 cell gene expression of IL-4, IL-5, and IL-13, but had no effect on IFN-gamma or IL-10 in animals inoculated with S. mansoni ova, larvae from the filarial helminth Brugia malayi, or CFA. Anti-B7-1 administration had no effect on CD4 cell transcript levels of IL-4 and IL-5, but inhibited IFN-gamma in mice inoculated with ova. Similar effects of anti-B7-2 on CD4 cell cytokine expression were observed in IL-4 knockout mice, indicating the existence of an alternative pathway for induction and/or expression of these cytokine genes. These findings suggest a possible role for anti-B7-2 in the therapy of infectious and atopic diseases in which immunopathologic reactions are mediated by selected Th2 cytokines.

Animals↗

PubMed1997

Targeted disruption of the chemokine eotaxin partially reduces antigen-induced tissue eosinophilia.

The chemokines are a large group of chemotactic cytokines that regulate leukocyte trafficking and have recently been shown to inhibit human immunodeficiency virus entry into cells. Eotaxin is a C-C chemokine implicated in the recruitment of eosinophils in a variety of inflammatory disorders and, unlike all other eosinophil chemoattractants, is eosinophil specific. However, given the large number of chemoattractants that have activities on eosinophils, it is unclear whether eotaxin has an important role in vivo. Furthermore, it remains unclear why there is constitutive expression of eotaxin in healthy states in the absence of eosinophilic inflammation. To begin to determine the significance of eotaxin at baseline and during eosinophil-mediated disease processes, we have used targeted gene disruption to generate mice that are deficient in eotaxin. Such mice demonstrate that eotaxin enhances the magnitude of the early (but not late) eosinophil recruitment after antigen challenge in models of asthma and stromal keratitis. Surprisingly, a role for eotaxin in regulating the constitutive number of eosinophils in the peripheral circulation is also demonstrated. These results indicate a contributory role for eotaxin in the generation of peripheral blood and antigen-induced tissue eosinophilia.

Animals↗

PubMed1997

IL-12 exacerbates helminth-mediated corneal pathology by augmenting inflammatory cell recruitment and chemokine expression.

Corneal inflammation (keratitis) is a major cause of visual impairment in Onchocerca volvulus infection. Previous studies showed that onchocercal keratitis can be induced in mice following s.c. immunization and intracorneal injection with soluble O. volvulus Ags (OvAg), and that the inflammatory response is dependent on T cells and IL-4. Since recombinant IL-12 impairs IL-4-dependent, Th2-mediated responses in other parasitic infections and in models of allergic asthma, the present study was undertaken to determine the effect of IL-12 on onchocercal keratitis. Mice were injected i.p. with IL-12 or saline at the time of initial sensitization to OvAg. Surprisingly, IL-12 treatment caused significant exacerbation of corneal pathology, which was associated with increased eosinophil and mononuclear cell infiltration into the corneal stroma. Consistent with the well-documented effect of IL-12 on Th1 cell development, corneas of IL-12-treated animals had elevated expression of the Th1 cytokine IFN-gamma and diminished expression of the Th2 cytokines IL-4, IL-5, IL-10, and IL-13. However, corneas from these animals also had marked elevation of alpha- and beta-chemokines known to be active on eosinophils and mononuclear cells, including IFN-gamma-inducible protein (IP)-10, macrophage inflammatory protein-1alpha, macrophage inflammatory protein-1beta, JE/monocyte chemotactic protein-1, RANTES (regulated upon activation, normal T expressed and secreted), and eotaxin. Together, these data indicate that IL-12 exacerbates OvAg-mediated corneal pathology by enhancing chemokine expression and recruitment of inflammatory cells.

Animals↗

PubMed1997

Identification of an epitope of a recombinant Onchocerca volvulus protein that induces corneal pathology.

Ocular onchocerciasis results from immune recognition of parasite proteins released into the eye by degenerating microfilariae. Previous studies have shown that pathology similar to human ocular onchocerciasis can be induced in sensitized mice by intracorneal injection with Onchocerca volvulus antigens. In the current study, we used this murine model to map the segments of O. volvulus protein disulfide isomerase (OvPDI) associated with the development of corneal pathology. Subclones of OvPDI were constructed encompassing one or more predicted T cell epitopes. Keratitis was induced in BALB/c mice after subcutaneous immunizations with OvPDI, followed by intracorneal challenge of OvPDI constructs. Truncated OvPDI proteins containing amino acids 450-481 of OvPDI were found to induce keratitis, whereas constructs that did not include this region did not induce corneal pathology. Consistent with this observation, two peptides derived from the 450-481 region stimulated T cell proliferation to a greater degree than control carrier protein. DNA sequence analysis of cDNAs encoding OvPDI from blinding and non-blinding strains of O. volvulus indicated no differences in the primary amino acid sequence of the 450-481 domain. Immunization of animals with OvPDI induced antibodies recognizing a 55 kDa host protein, identical to the predicted molecular weight of the mouse PDI homologue. Together, these data implicate specific antigenic epitopes of OvPDI in the development of O. volvulus mediated corneal pathology.

Amino Acid Sequence↗

PubMed1997

Immunopathology of onchocerciasis: a role for eosinophils in onchocercal dermatitis and keratitis.

This review has sought to demonstrate that eosinophils have an important role in the immunopathology of onchocercal dermatitis and keratitis. The most compelling evidence is the consistent presence of eosinophils and eosinophil granule proteins at the site of tissue damage, either after parasite death or direct injection of parasite antigens. A more definitive role for eosinophils in onchocercal keratitis will be determined using IL-5 gene knockout mice (an animal model of onchocercal dermatitis has yet to be established). Identification of chemoattractants and adhesion molecules necessary for eosinophil recruitment will indicate possible approaches to immune intervention.

Animals↗

PubMed1997

Pleomorphism of stromal eosinophils in murine experimental onchocercal keratitis.

Onchocercal keratitis (river blindness) is one of the leading worldwide causes of blindness. Light microscopic analysis of human specimens and corneal tissue from experimental models has implicated the eosinophil as an important cell in the inflammatory response. Our previous studies in experimental murine onchocercal keratitis have demonstrated that the inflammatory infiltrate is composed primarily of eosinophils displaying ring shaped or bilobed nuclei. However, a number of cells were not characterizable by light microscopy, presumably due to mechanical distortion. To more fully characterize the inflammatory cell infiltrate, we examined corneal specimens by transmission electron microscopy. In addition to typical eosinophils with bilobed and ring shaped nuclei, this approach revealed cells with variable nuclear morphology and cell shape which contained the dense cored granules characteristic of eosinophils. Hence, the degree of pleomorphism of eosinophils is broader than appreciated and underscores the importance of this cell in experimental murine onchocercal keratitis.

Animals↗

PubMed1996

Expression of hyaluronidase by tumor cells induces angiogenesis in vivo.

Hyaluronic acid is a proteoglycan present in the extracellular matrix and is important for the maintenance of tissue architecture. Depolymerization of hyaluronic acid may facilitate tumor invasion. In addition, oligosaccharides of hyaluronic acid have been reported to induce angiogenesis. We report here that a hyaluronidase similar to the one on human sperm is expressed by metastatic human melanoma, colon carcinoma, and glioblastoma cell lines and by tumor biopsies from patients with colorectal carcinomas, but not by tissues from normal colon. Moreover, angiogenesis is induced by hyaluronidase+ tumor cells but not hyaluronidase- tumor cells and can be blocked by an inhibitor of hyaluronidase. Tumor cells thus use hyaluronidase as one of the "molecular saboteurs" to depolymerize hyaluronic acid to facilitate invasion. As a consequence, breakdown products of hyaluronic acid can further promote tumor establishment by inducing angiogenesis. Hyaluronidase on tumor cells may provide a target for anti-neoplastic drugs.

Animals↗

PubMed1996

Onchocerca volvulus-mediated keratitis: cytokine production by IL-4-deficient mice.

Corneal inflammation similar to human onchocercal keratitis can be induced in mice by subcutaneous immunization of a soluble extract of Onchocerca volvulus (OvAg) followed by direct injection of OvAg into the corneal stroma. Previous studies have shown that corneal pathology is associated with increased systemic and corneal Th2 cytokine expression and that IL-4 gene knockout (IL-4-/-) mice develop less severe or no O. volvulus-mediated keratitis. The current study examined the contribution of Th2 cytokines to the diminished OvAg-induced corneal immunopathology observed in IL-4-/- mice. IL-4-/- mice (129Sv x C57B1/6), wild-type F2 littermates (IL-4+/+), and C57B1/6 mice were sensitized by repeated subcutaneous immunization with OvAg. Ten days after the final immunization, mice were sacrificed, spleens were removed, and cells were incubated with OvAg. Cells from immunocompetent C57B1/6 and IL-4+/+ mice produced IL-4 and IL-5, but no IFN-gamma, whereas cells from IL-4-/- mice had elevated IFN-gamma and no IL-4. Interestingly, cells from these animals produced levels of IL-5 protein equivalent to those of C57B1/6 and IL-4+/+ mice. To determine cytokine production in corneas during the onset of onchocercal keratitis, OvAg-immunized mice were injected intracorneally with OvAg, and cytokine gene expression in the cornea was determined by RT-PCR. Temporal analysis of cytokine gene expression in corneas of immunocompetent mice showed that the Th2-associated cytokines IL-4, IL-5, IL-10, and IL-13 were produced within 1 day of intrastromal injection, with sustained elevations for 10 days. Maximal IFN-gamma mRNA levels were not detected until Day 10. This was in contrast to IL-4-/- mice in which IFN-gamma appeared at Day 1 and remained elevated for at least 10 days. Moreover, in corneas from IL-4-/- mice, all Th2 cytokines with the exception of IL-4 were up-regulated and expressed with kinetics similar to that of IL-4+/+ littermates. Histologically, corneas from IL-4-/- mice were less edematous and contained fewer eosinophils and other inflammatory cells than those from immunocompetent controls. As there was no difference in peripheral eosinophil levels, these data indicate that the diminished severity of onchocercal keratitis in IL-4-/- mice is not due to failure to develop systemic or local Th2 cytokine responses or to produce eosinophils, but that IL-4 may be involved in recruitment of eosinophils and other inflammatory cells into the corneal stroma.

Animals↗

PubMed1996

Experimental onchocercal keratitis.

In individuals with onchocerciasis, severe visual impairment (river blindness) occurs as a result of corneal inflammation induced by antigens released from dead and dying Onchocerca volvulus microfilariae. To characterize the underlying immune response, animal models have been developed that partially reproduce many of the clinical features of human onchocercal keratitis, Eric Pearlman here discusses how these studies have identified systemic and local immune responses associated with keratitis, including T helper-cell subset and cytokine responses.

Journal Article↗

PubMed1996

Factors associated with response to platelet transfusion following hematopoietic stem cell transplantation.

We studied 526 consecutive post-transplant platelet transfusions to determine the factors associated with response to platelet transfusion in the BMT setting. Poor responses to platelet transfusions occurred frequently, with 310 of the 484 evaluable transfusions (64%) resulting in post-infusion corrected count increments of less than 7500. Factors associated with poor response to platelet transfusion by both univariate and multivariate analysis included, (1) presence of serum lymphocytotoxic antibodies; (2) male sex; (3) body surface area greater than 1.7 m2; (4) transfusion of red cells on the day of the platelet infusion; (5) concurrent administration of steroids; (6) major ABO mismatch between the recipient and the platelet product; and (7) (among women) a history of one or more pregnancies prior to transplant. Paradoxically, a history of greater than 25 blood product exposures prior to transplant, and evidence of prior CMV infection in either the bone marrow donor or recipient were associated with higher CCIs by both univariate and multivariate analysis. Factors that showed little correlation with response to platelet transfusion included, (1) age of the infused platelet product; (2) concurrent fever; (3) recent administration of intravenous immunoglobulin; and (4) absolute neutrophil count at the time of the infusion. The factors associated with response to platelet transfusion in BMT patients appear to be different from those observed in the non-transplant setting.

ABO Blood-Group System↗

PubMed1995

Interleukin 4 and T helper type 2 cells are required for development of experimental onchocercal keratitis (river blindness).

Inflammation of the corneal stroma (stromal keratitis) is a serious complication of infection with the nematode parasite Onchocerca volvulus. Because stromal keratitis is believed to be immunologically mediated in humans, we used a murine model to examine the role of T cells and T helper cell cytokines in the immunopathogenesis of these eye lesions. BALB/c mice immunized subcutaneously and injected intrastromally with soluble O. volvulus antigens (OvAg) developed pronounced corneal opacification and neovascularization. The corneal stroma was edematous and contained numerous eosinophils and mononuclear cells. Stromal keratitis in immunized mice was determined to be T cell dependent based on the following observations: (a) T cell-deficient nude mice immunized and injected intrastromally with OvAg fail to develop corneal pathology; and (b) adoptive transfer of spleen cells from OvAg-immunized BALB/c mice to naive nude mice before intrastromal injection of OvAg results in development of keratitis. OvAg-stimulated lymph node and spleen cell cytokine production was dependent on CD4 cells and included interleukin (IL)-4 and IL-5, but not interferon gamma, indicating a predominant T helper type 2 cell-like response. Inflamed corneas from immunized BALB/c mice and from reconstituted nude mice had greatly elevated CD4 and IL-4 gene expression compared with interferon gamma. Mice in which the IL-4 gene was disrupted failed to develop corneal disease, demonstrating that IL-4 is essential in the immunopathogenesis of O. volvulus-mediated stromal keratitis.

Animals↗

PubMed1995

Endogenous IL-12 is required for control of Th2 cytokine responses capable of exacerbating leishmaniasis in normally resistant mice.

We investigated the mechanisms by which treatment with anti-IL-12 Ab prevents cure of infection with Leishmania major in resistant C57BL/6 mice. Consistent with delayed production of IL-12, anti-IL-12 Abs could be administered as late as 2 wk after infection to exacerbate disease. Starting at 2 wk of infection, the cultured lymph node cells from mice treated with either polyclonal or monoclonal anti-IL-12 Abs persistently generated 3- to 10-fold more IL-4 and IL-10 in response to L. major Ag compared with cells from mice receiving preimmune goat IgG. Reciprocal decreases in Ag-specific IFN-gamma production were observed in mice receiving anti-IL-12 Abs. A similar reversal of IFN-gamma and IL-4 production accompanied progressive disease induced by pretreatment with a single dose of anti-IFN-gamma mAb. Although IFN-gamma production was suppressed for up to 4 wk in mice treated with monoclonal anti-IL-12 or anti-IFN-gamma, coadministration of neutralizing anti-IL-4 IgG reversed progressive illness. These findings demonstrate that IL-12 produced in vivo is necessary for both the emergence of IFN-gamma producing cells and the down-regulation of Th2 cell responses during murine leishmaniasis. Furthermore, the uninhibited production of IL-4 was required to sustain progressive infection initiated by the decreased IFN-gamma synthesis observed in anti-IL-12 and anti-IFN-gamma-treated mice.

Animals↗