The value of rheumatoid factor and anti-citrullinated protein antibodies as predictors of response to infliximab in rheumatoid arthritis: an exploratory study.

OBJECTIVE: It remains unclear whether autoantibodies are useful biomarkers to tailor the choice of biological treatment in RA. We investigated the relationship between the presence and levels of different RF and ACPA isotypes and the response to TNF blockade in an exploratory study. METHODS: A total of 101 active RA patients were prospectively treated with infliximab (3 mg/kg). Changes in disease activity were monitored by the 28-joint DAS (DAS-28). Serum levels of different isotypes [immunoglobulins M, G and A (IgM, IgG and IgA)] of RF and anti-citrullinated peptide antibodies were measured by ELISA. RESULTS: The mean DAS-28 decreased from 5.9 (1.1) at baseline to 4.0 (1.3) at Week 16 of infliximab treatment (P < 0.001). High baseline levels of different isotypes of RF (all P < 0.008), ACPA IgM (P = 0.008) and ACPA IgG (P = 0.07) were associated with an absolute decrease in DAS-28 after TNF blockade. This relationship persisted after adjusting for DAS-28 at baseline. However, the different isotypes of baseline RF and ACPA levels accounted for only a small proportion of variance in treatment response (RF: R² between 7 and 12% and ACPA: R² between 4 and 7%). The simultaneous presence of all three isotypes of RF or ACPA had no additive value. CONCLUSION: Presence as well as the titres of RF and IgM ACPA at baseline are significantly correlated with better response to infliximab treatment. However, this correlation is not strong enough to allow a reliable prediction in individual patients. Trial Registration. ISRCTN Register, http://www.controlled-trials.com/isrctn/, ISRCTN36847425.

Compartmental apoptosis and neutrophil accumulation in severe peritonitis.

BACKGROUND: Migration and activation of polymorphonuclear neutrophils (PMN) and apoptosis are central to inflammatory tissue damage. This study examines the relation of these processes, and their expression in the abdominal, systemic, and bronchoalveolar compartments in patients with severe peritonitis. MATERIALS AND METHODS: Thirty-one consecutive patients undergoing laparotomy for severe secondary peritonitis. Eight operated patients without peritonitis and 10 long-term mechanically ventilated noninfected patients served as controls. Peritoneal fluid, blood, and bronchoalveolar lavage fluid (BALF) was obtained on d 0 (day of initial laparotomy), 2, and 3. Levels of chemokines (interleukin (IL)-8 and monocyte chemotactic protein (MCP)-1), PMN-counts, PMN activation [myeloperoxidase (MPO), elastase] and apoptosis (nucleosomes) were determined. RESULTS: In peritonitis patients, levels of chemokines and markers of PMN sequestration were increased in all compartments. IL-8 levels were higher in BALF than in plasma, and did not originate from the circulation or from lysis of alveolar cells. Pulmonary nucleosome levels were higher in patients who died (P=0.020), and corresponded with PMN-count in BALF (P<0.001), levels of chemokines (IL-8, P=0.003; MCP-1, P=0.001), and PMN-activation (MPO, P<0.001; elastase P=0.007). CONCLUSION: Severe peritonitis produces an early pulmonary expression of chemoattractants creating a gradient for PMN sequestration and activation into the lung. These parameters are associated with expression of apoptosis in the lung, which is increased in nonsurviving peritonitis patients.

Differential responses of cellular immunity in patients undergoing neoadjuvant therapy followed by surgery for carcinoma of the oesophagus.

BACKGROUND: To compare immune responses following neoadjuvant chemoradiation therapy in combination with hyperthermia plus surgery to those induced by surgery alone in patients with oesophageal cancer. METHODS: Thirty-two patients with histopathologically proven oesophageal cancer, scheduled for potentially curative transhiatal or transthoracic oesophagectomy with (neo, n = 20) or without (control, n = 12) neoadjuvant thermochemoradiation therapy (ThCR) were included. Peripheral blood samples were obtained before ThCR, after 2 weeks of ThCR, 1 day before surgery, on postoperative days 1, 3, 7, and 6 weeks after surgery, for white blood cell counts, lymphocyte subsets and T helper type 1 (Th1) and type 2 (Th2) lymphocyte responses. RESULTS: Neo patients showed a significant decrease in granulocytes and lymphocyte subsets, and T cell cytokines after 2 weeks of ThCR. Only CD8+ (cytotoxic) T cells recovered after ThCR to reach normal levels prior to surgery. In contrast, CD4+ T (helper) cells, and NK- and B cells in neo patients did not recover prior to surgery (all P < 0.05). Oesophagectomy induced a significant increase in granulocytes and a decrease in lymphocytes (and subsets). Only those subsets that had not recovered after ThCR (CD4+ T cells, NK and B cells but not CD8+ T cells), were significantly lower (all P < 0.05) during the entire postoperative study period. Postoperatively, the stimulated cytokine production capacity of Th1 and Th2 cells, corrected for number of T cells, was not significantly different between the groups. CONCLUSION: Neoadjuvant thermochemoradiation for oesophageal cancer caused significant disturbances of host cellular immunity with reduced T, NK and B cell counts, and differential recovery of cytotoxic and helper T cells leading to prolonged T cell imbalance that extends beyond the time of surgery. The functional and anti-tumour consequences of this immunodisturbance need further investigation, as recovery of T helper cytokine production towards surgery was less impaired than T helper cell counts.

Repeatability of inflammatory parameters in induced sputum of COPD patients.

RATIONALE: Limited information is available on repeatability of inflammatory parameters in whole induced sputum samples from patients with COPD. OBJECTIVES: To study short-term and long-term repeatability in induced sputum samples in 22 patients with moderate to severe, stable COPD (mean age 64 yr, mean FEV(1) 1.91 L=65% of predicted). Samples were collected on 71 occasions twice within 1 to 7 days (mean 3.8 days) and on 12 occasions twice with an interval of 3 months while clinically stable. Cell differentials, markers of neutrophilic and eosinophilic inflammation, respiratory membrane permeability and size-selective permeation were assessed. FINDINGS: Parameters of permeability and of size-selective permeation, % eosinophils and % neutrophils showed the best short-term repeatability with intra-class correlation coefficients (Ri) of 0.61 to 0.90, followed by total cell count (TCC) with Ri of 0.52. Repeatability of soluble cell activation markers was less satisfactory (Ri 0.34 to 0.52). Mean short-term within-patient variability for TCC and permeability was approximately 2-fold and for cell activation markers 3-fold; mean between-patients variability was twice as high. Inducing sputum slightly enhanced eosinophil numbers and % neutrophils and decreased % macrophages in successive IS samples. Long-term repeatability was comparable to short-term repeatability but variability increased. CONCLUSIONS: Repeatability of parameters assessed in whole sputum is similar as reported previously for sputum plugs. In COPD an induced sputum procedure has a minor pro-inflammatory effect. The current data facilitates power calculations but also indicates that studies using inflammatory markers in sputum may easily be underpowered.

Characterization of CD4+ memory T cell responses directed against common respiratory pathogens in peripheral blood and lung.

BACKGROUND: We investigated CD4(+) memory T cell responses to influenza virus (FLU), respiratory syncytial virus (RSV), and nontypeable Haemophilus influenzae (NTHi). METHODS: The precursor frequencies of antigen-specific CD4(+) cells were determined by in vitro expansion of peripheral blood mononuclear cells from healthy individuals (n=9) and patients with chronic obstructive pulmonary disease (COPD; n=16). The expression of CD27 and CCR7 and the production of interferon (IFN)- gamma and interleukin-2 was measured directly ex vivo. Furthermore, the phenotypic and functional properties of CD4(+) T cells residing in the lung were analyzed and compared with those of circulating CD4(+)memory cells from the same donors (n=8). RESULTS: FLU-, RSV-, and NTHi-specific CD4(+) memory T cells circulated at low frequencies in the peripheral blood of healthy individuals and patients. RSV- and NTHi-specific CD4(+) T cells had a memory phenotype with moderate to high CD27 and CCR7 expression. In contrast to the low frequencies of circulating FLU-specific CD4(+) T cells, we found an enrichment of differentiated CD4(+) FLU-specific cells and high IFN- gamma expression in CD4(+) memory cells in lung tissue. CONCLUSION: No gross defects were found in circulating CD4(+) memory cells specific for pathogens associated with COPD. However, the large differentiated CD4(+) memory T cell pool residing in the lung may contribute to a large extent to local antiviral immunological protection.

Selective accumulation of differentiated CD8+ T cells specific for respiratory viruses in the human lung.

The lungs are frequently challenged by viruses, and resident CD8(+) T cells likely contribute to the surveillance of these pathogens. To obtain insight into local T cell immunity to respiratory viruses in humans, we determined the specificity, phenotype, and function of lung-residing CD8(+) T cells and peripheral blood CD8(+) T cells in a paired analysis. The lung contained markedly higher frequencies of influenza (FLU)-specific and respiratory syncytial virus (RSV)-specific CD8(+) T cells when compared with the circulation. This contrasted with an equal distribution of cytomegalovirus- and Epstein-Bar virus-specific CD8(+) T cells. Noticeably, a substantial fraction of the lung-residing FLU- and RSV-specific CD8(+) T cells had progressed to a relatively late differentiation phenotype, reflected by low expression of CD28 and CD27. Lung-derived FLU-specific CD8(+) T cells had low activation requirements, as expansion of these cells could be initiated by cognate peptide in the absence of helper cell-derived signals. Thus, the human lung contains high numbers of differentiated FLU- and RSV-specific memory CD8(+) T cells that can readily expand upon reexposure to virus. Resident lung T cells may provide immediate immunological protection against pulmonary virus infections.

Effect of cetirizine dihydrochloride on the airway response to hypertonic saline aerosol in patients with chronic obstructive pulmonary disease (COPD).

Hypertonic saline aerosol can elicit airway obstruction in patients with moderate or severe COPD. In the present study we assessed whether cetirizine dihydrochloride is capable of modulating this response. After a screening visit, 20 patients with COPD (mean FEV(1) 49% pred) were treated with cetirizine 10mg daily or placebo over 1 week in a randomized, double-blind, cross-over fashion and measurements performed at the end of treatment periods. At each visit, patients were challenged by 3% saline aerosol (screening: 0.9%) over 5 min after prior inhalation of salbutamol, and 45 min later sputum was obtained after inhalation of 0.9% saline. Lung function was quantified in terms of forced expiratory (FEV(1)) and inspiratory (FIV(1)) volumes. Spirometric values did not differ between visits and salbutamol-induced bronchodilation was not altered by cetirizine. Compared to baseline or post-salbutamol values, the saline-induced fall in FEV(1) was smallest at screening (P<0.01), without a significant difference between treatments. Regarding FIV(1), however, the percent fall from baseline was higher after placebo (Delta=-10.1%; P<0.05) compared to screening (0.4%) or cetirizine (-4.3%). Sputum composition showed no significant differences except for a tendency towards reduced concentrations of alpha(2)-macroglobulin after cetirizine compared to placebo (P=0.045). The present data indicate some, though small, effects of the H1 receptor antagonist cetirizine on hypertonic saline-induced airway obstruction in patients with moderate-to-severe COPD. In view of the mechanisms involved, it is an open question whether stronger effects can be elicited with higher doses and whether such effects would translate into clinical benefits, e.g. during exacerbations.

Respiratory syncytial virus-specific CD8+ memory T cell responses in elderly persons.

BACKGROUND: We investigated respiratory syncytial virus (RSV)-specific CD8(+) memory T cell responses in healthy control participants (n=31) and in patients with chronic obstructive pulmonary disease (COPD) (n=9), with respect to frequency, memory phenotype, and proliferative requirements. METHODS: The properties of RSV-specific CD8(+) T cells were analyzed by use of RSV tetramers. The proliferative requirements of RSV-specific CD8(+) T cells were analyzed by culture of peripheral-blood mononuclear cells with RSV peptide in combination with distinct cytokines. RESULTS: RSV-specific CD8(+) memory T cells showed a high level of expression of CD27 and interleukin-7R alpha and a low level of expression of CCR7. In the healthy participants, the frequency of RSV tetramer(+) CD8(+) T cells was significantly lower than the frequency of influenza virus A (FLU) tetramer(+) CD8(+) T cells (P=.0001). In contrast to FLU tetramer(+) CD8(+) T cells, we could detect RSV tetramer(+) CD8(+) T cells in the subgroup of elderly healthy participants (age, > or =55 years) and in the patients with COPD only after in vitro expansion. Expanded RSV-specific T cells produced interferon- gamma and granzyme B. CONCLUSION: We provide evidence that a pool of functional RSV-specific CD8(+) memory T cells persists in the peripheral blood of healthy individuals and patients with COPD. Low numbers of RSV-specific memory T cells in the elderly and in patients with COPD may explain the increased susceptibility to RSV infection in these populations.

IgG and complement receptor expression in children treated by peritoneal dialysis.

Children treated by peritoneal dialysis (PD) are at increased risk of infections. IgG receptors (FcgammaRs) and complement receptors (CRs) on white blood cells (WBCs) are important for the phagocytic process. We have investigated FcgammaR and CR expression on monocytes, macrophages and neutrophils in blood and in peritoneal dialysis effluent (PDE) of 39 PD children. WBCs were isolated from blood and PDE, labelled with FITC-conjugated CD16 (FcgammaRIII), CD32 (FcgammaRII), CD64 (FcgammaRI), CD11b (CR3) and CD35 (CR1) monoclonal antibodies, and analysed by flow cytometry. Peritoneal cells had lower percentages of FcgammaR-positive or CR-positive cells than blood. On the other hand, the receptor number per cell [mean fluorescence intensity (MFI)] was higher on peritoneal macrophages and neutrophils than blood, except for CD16. The FcgammaR and CR expression in blood and dialysate did not change significantly during the first year of PD treatment. During a peritonitis episode the MFI of all receptors in blood increased only on monocytes, with the exception of CD32. The percentages of FcgammaR-positive and CR-positive macrophages and neutrophils in the PDE increased, whereas the MFI did not increase consistently. Peritoneal cells of PD children showed a lower percentage of FcgammaR-positive and CR-positive neutrophils and macrophages, combined with an increased MFI, indicating a state of activation. Blood and peritoneal cells are capable of up-regulating the receptor expression during peritonitis but probably not to a maximum level.

Human CD8(+) T cell responses against five newly identified respiratory syncytial virus-derived epitopes.

CD8(+) T lymphocytes play a major role in the clearance of respiratory syncytial virus (RSV) infections. To be able to study the primary CTL response in RSV-infected children, epitopes presented by a set of commonly used HLA alleles (HLA-A1, -A3, -B44 and -B51) were searched for. Five epitopes were characterized derived from the matrix (M), non-structural (NS2) and second matrix (M2) proteins of RSV. All epitopes were shown to be processed and presented by RSV-infected antigen-presenting cells. HLA-A1 tetramers for one of these epitopes derived from the M protein were constructed and used to quantify and phenotype the memory CD8(+) T cell pool in a panel of healthy adult donors. In about 60 % of the donors, CD8(+) T cells specific for the M protein could be identified. These cells belonged to the memory T cell subset characterized by expression of CD27 and CD28, and down-regulation of CCR7 and CD45RA. The frequency of tetramer-positive cells varied between 0.4 and 3 per 10(4) CD8(+) T cells in PBMC of healthy asymptomatic adult donors.

IGG and complement receptor expression on peripheral white blood cells in uraemic children.

BACKGROUND: Phagocytosis of IgG- or complement-opsonized bacteria and antibody production by lymphocytes are regulated by cell surface receptors for IgG (FcgammaRI, FcgammaRII and FcgammaRIII) and complement (CR1 and CR3). We measured the effect of uraemia and dialysis treatment on FcgammaR and CR expression on leukocytes in blood. METHODS: Blood samples were obtained from children: 40 treated with peritoneal dialysis (PD), 23 with haemodialysis (HD), 46 not yet dialysed (CRF) and 33 healthy (HC). White blood cells, isolated from EDTA-blood by centrifugation after cell fixation with paraformaldehyde, were labelled with FITC-conjugated CD16 (FcgammaRIII), CD32 (FcgammaRII), CD64 (FcgammaRI), CD11b (CR3) and CD35 (CR1) monoclonal antibodies and analysed by flow cytometry. RESULTS: In PD, HD, CRF and HC, monocytes and neutrophils were all positive for FcgammaR and CR, except for CD16 on monocytes (20% positive). Lymphocytes expressed CD16 and CD32 but not CD64. PD, HD and CRF children had lower percentages of CD16(+) and CD32(+) lymphocytes compared with HC. The percentage of CD11b(+) lymphocytes was lower only in PD and the percentage of CD35(+) lymphocytes was lower in HD and CRF compared with HC. The median CD32 mean fluorescense intensity (MFI) on lymphocytes, monocytes and neutrophils was lower in PD, HD and CRF compared with HC. On the other hand, CD11b MFI on lymphocytes, monocytes and neutrophils was higher in PD, HD and CRF children compared with HC. CD16 and CD64 MFI were not different among the groups and CD35 MFI was only lower on lymphocytes from PD, HD and CRF compared with HC. CONCLUSIONS: In children with chronic renal failure, whether dialysed or not, FcgammaRII expression on lymphocytes, monocytes and neutrophils was reduced and CR3 expression was increased. Furthermore, CR1 expression on lymphocytes, important for the humoral response, was lower in children with renal failure. Age and uraemia are associated with these abnormalities and might contribute to impaired immune function in children with chronic renal failure.

Lymphocyte subsets and T(h)1/T(h)2 immune responses in patients with adenocarcinoma of the oesophagus or oesophagogastric junction: relation to pTNM stage and clinical outcome.

INTRODUCTION: Recent studies have indicated that the cytokines produced by CD4(+) T helper type 1 (T(h)1) and type 2 (T(h)2) cells are critically important in antitumour immunity and perhaps clinical outcome. From this perspective, we investigated the immunocompetence of patients with previously untreated cancer of the oesophagus or oesophagogastric junction (OGJ) in relation to stage of disease and postoperative survival. METHODS: Blood samples were taken prior to surgery from 32 patients with adenocarcinoma of the oesophagus or OGJ. Ten healthy volunteers served as normal controls. T-cell and monocyte subpopulations were determined using flow cytometry. Monocyte as well as T(h)1- and T(h)2-lymphocyte cytokine levels were assessed in stimulated whole blood cultures. RESULTS: Absolute T-cell and monocyte (subset) counts as well as monocyte cytokine levels were similar among patients and controls. Production of T(h)1-type cytokines was higher in patients than in controls (IFN-gamma, p=0.01; IL-2, p=0.05), whereas T(h)2-type cytokine levels were comparable (IL-4, p=0.5; IL-13, p=0.3). T-cell CD4(+)/CD8(+) ratios decreased as pTNM stage worsened (stage I/II vs stage III/IV, p=0.009). Of all measured immunological parameters, only IL-2 production significantly affected both overall survival ( p=0.015) and disease-free survival ( p=0.0062). High IL-2 levels corresponded with a favourable prognosis. CONCLUSIONS: Patients awaiting surgery for adenocarcinoma of the oesophagus or oesophagogastric junction demonstrated a shift in the T(h)1/T(h)2 balance-in favour of T(h)1-compared with healthy volunteers. The ability of T cells to produce IL-2 was related to survival indicating a crucial role of T(h)1-type cells in antitumour immunosurveillance.

Comparison of allergen-induced late inflammatory reactions in the nose and in the skin in house dust mite-allergic patients with or without asthma.

BACKGROUND: It remains to be established which factors contribute to the occurrence of asthma in allergic individuals. We hypothesized that differences in the late allergic inflammatory reaction to allergen between asthmatic and non-asthmatic house dust mite-allergic individuals might contribute to the difference in the clinical presentation of allergy. AIM: To compare allergen-induced changes in parameters for cellular inflammation during the phase of the late allergic reaction in the skin and nose, in house dust mite-allergic individuals with or without asthma. MATERIAL AND METHODS: Nasal and dermal allergen challenges with house dust mite (Dermatophagoides pteronyssinus) extract were performed in 52 house dust mite-allergic individuals, of whom 26 had mild to moderate persistent asthma and 26 had perennial rhinitis without current or past asthmatic symptoms. Serial nasal lavage samples were analyzed for the presence of inflammatory cells (eosinophils and neutrophils) and soluble markers associated with cellular inflammation [interleukin-5 (IL-5), interleukin-8 (IL-8), eosinophil cationic protein (ECP) and myeloperoxidase (MPO)]. Macroscopic late phase skin reactions were studied after intracutaneous skin tests with house dust mite extract. RESULTS: Fixed dose nasal allergen provocation elicited a similar degree of immediate allergic reaction as judged by plasma protein exudation and histamine concentrations in asthma and non-asthmatic rhinitis. Subsequently, no differences between groups were found during the phase of the late allergic reaction (4-24 h) in inflammatory cell influx, plasma protein leakage, ECP or MPO. Likewise, there were no differences in levels of chemotactic cytokines IL-5 and IL-8. In agreement with the results of nasal challenge, the late skin reaction after dermal challenge with a fixed allergen dose and after an allergen dose 10,000 times above the skin threshold for an early skin reaction did not differ between the groups. CONCLUSION: House dust mite-allergic patients with or without asthma have very similar late allergic inflammatory reactions in the skin and in the nose after allergen challenge. Hence, it is unlikely that the occurrence of pulmonary symptoms in asthma is explained by a general tendency of asthmatics to have an enhanced late allergic cellular inflammatory response. Nasal and dermal allergen provocations are adequate models to study allergen-induced inflammation but probably lack the pivotal link which is essential for the development of asthma.

Immune responses and prediction of major infection in patients undergoing transhiatal or transthoracic esophagectomy for cancer.

OBJECTIVE: To investigate alterations in immune responses after transhiatal versus transthoracic esophageal resection and to evaluate the role of preoperative immune functions in predicting postoperative infectious complications. SUMMARY BACKGROUND DATA: Impaired immune defense is associated with a decreased resistance to infection. Patients undergoing esophageal resection via a transhiatal or transthoracic approach are prone to develop infectious complications. There are no randomized data on immune responses after two major surgical interventions. METHODS: The study group consisted of 20 patients who were randomly allocated to a limited transhiatal or extended transthoracic esophagectomy for cancer. Blood samples were taken before the operation and at regular intervals thereafter from day 1 to day 10. Monocyte and T-helper type 1 (Th1) and type 2 (Th2) lymphocyte functions were assessed in stimulated whole blood cultures. RESULTS: Both surgical groups had severely depressed in vitro production of interleukin (IL)-12, IL-10, interferon-gamma, IL-2, IL-4, and IL-13 on postoperative day 1. Depression of Th2-type cytokine production was more profound after transthoracic than after transhiatal esophagectomy (IL-4, P=.005; IL-13,P=.007). Postoperative reduction in Th1-type cytokine production was similar between the two groups (interferon-gamma, P=.40; IL-2, P=.06). Irrespective of the surgical approach, patients who developed major infectious complications after surgery presented with a diminished T-cell cytokine production before the operation compared to those who had a relatively uneventful recovery (IL-4, P=.045; interferon-gamma, P=.064). In regression analysis, the occurrence of postoperative major infection was best predicted by increased duration of anesthesia ( P<.0001) and low preoperative interferon-gamma production ( P=.006). CONCLUSIONS: Both transhiatal and transthoracic esophagectomy induced severely depressed monocyte and T-lymphocyte cytokine production. The extent of the surgical procedure had a differential immunosuppressive impact on Th2-type but not on Th1-type cell activity, indicating that the two Th pathways were downregulated through distinct mechanisms. Preoperative interferon-gamma determination would be useful to anticipate the occurrence of postoperative major infectious complications.

Local T-cell activation after segmental allergen challenge in the lungs of allergic dogs.

Dogs with immunoglobulin E (IgE) allergy for ragweed that are sensitized by intrapulmonary exposure to ragweed can be used to study the pulmonary immune response that is important in allergic asthma. Using this model, we tested the hypothesis that T lymphocytes are activated locally in the airways shortly after allergen exposure of the lungs. The airways of six allergic dogs and three non-allergic dogs were exposed to ragweed by segmental allergen challenge (SAC). T-cell subsets and T-cell activation in blood and bronchoalveolar lavage (BAL) fluid were measured by flow cytometry before SAC and at 4, 24 and 72 hr thereafter. SAC caused a statistically significant increase in the percentage of major histocompatibility complex (MHC) class II-positive CD4 and CD8 T cells in BAL fluid and a significant increase in the mean fluorescent activity of MHC class II from 4 hr after SAC onward. This activation was significantly different from that found in cells from lung lobes challenged with saline, or from lung lobes in non-allergic dogs challenged with ragweed. The percentage of CD45RA(bright) CD8 cells increased significantly in allergic dogs after both ragweed and saline challenges. This was significantly higher than in non-allergic dogs. We conclude that T-cell activation in the airways of dogs can be measured after in vivo activation of the cells by measuring MHC class II and CD45RA expression in BAL fluid T cells. Furthermore, in allergic dogs, T cells are activated locally in the lungs within 4 hr after exposure to ragweed allergen. These results suggest a role for T lymphocytes in the development of late-phase allergic reactions in the airways.

Products from human mast cell line cells enhance the production of interferon-gamma by CD8+ and CD4+ T cells.

In patients with allergic asthma, T-cell cytokines are implicated in the regulation of the local inflammation in the airways. The ability of sensitized mast cells to release mediators and cytokines early upon allergen stimulation makes them important candidates for local immunoregulation. We have studied the effects of human mast cells on T cells with the use of the human mast cell line HMC-1. We showed that activated human mast cells or their soluble products induced and enhanced the interferon-gamma (IFN-gamma) production by T cells up to about 60-fold. The production of interleukin (IL)-4 was hardly affected and that of IL-5 was slightly enhanced. The enhancement of IFN-gamma production was induced both in polyclonal CD4+ and CD8+ T cells and in CD4+ and CD8+ T-cell clones. Further characterization of the factors involved demonstrated a molecular mass above 30 000. Our results implicate that by this mechanism mast cells may account for a negative feedback system locally down-regulating allergen-induced T helper 2 responses via IFN-gamma production by the T cells.