Frequency of Th1, Th2 and Th17 producing T lymphocytes in bronchoalveolar lavage of patients with systemic sclerosis.

OBJECTIVE: The pathophysiology of the lung fibrotic process in systemic sclerosis (SSc) is not fully elucidated. Since this pattern represents the leading cause of death in SSc, the knowledge of its actual pathophysiology is basic to prevent and stage pulmonary damage. In this study, we aimed to further investigate the relationship between the functional profiles of bronchoalveolar lavage (BAL) T cells and the pulmonary manifestation of the disease. METHODS: With this aim, we assessed the frequency of Th1, Th2 and Th17 producing T-lymphocytes and their effector cytokines in BAL of SSc patients without signs or symptoms of lung interstitial involvement (SScFib-) and with interstitial lung fibrosis (SScFib+). We also study as control groups: patients with usual interstitial pneumonia (UIP), patients with sarcoidosis and 9 healthy controls (NHCs). RESULTS: SScFib- showed an increase in BAL Th1/Th2 balance compared to NHCs, which was even higher than that observed in sarcoidosis. SScFib+ showed a shift towards a lower Th1/Th2 ratio as compared to SScFib-. The frequency of Th17 BAL T cells did not change among study groups. CONCLUSION: Our data confirm the Th1/Th2 imbalance hypothesis on the pathogenesis of interstitial fibrosis in SSc patients, and suggest a possible utility in the assessment of BAL Th1/Th2 ratio.

Lung transplantation: the role of azithromycin in the management of patients with bronchiolitis obliterans syndrome.

Bronchiolitis obliterans syndrome (BOS) is the leading cause of death in lung transplant recipients (LTR). BOS is thought to result from chronic immunologic/inflammatory insults leading to peri-bronchiolar leukocyte infiltration, with a subsequent exuberant tissue re-modelling and fibro-obliteration of the luminal space of the allograft airways. Diagnosis is based on functional criteria and severity is graded on the degree of Forced Expiratory Volume in 1 second (FEV1) impairment. Current strategies to improve pulmonary function once BOS is established have demonstrated little or no impact on disease progression and re-transplantation remains the only therapeutic option. Among the alternative treatments which have been attempted in the last few years, long-term azithromycin treatment seems to be the most promising therapeutic device for BOS treatment. Azithromycin is a macrolide antibiotic, endowed with a broad spectrum of anti-inflammatory/immunomodulatory activities. Long-term oral azithromycin therapy can significantly improve FEV1 in about 42% of patients with established BOS. Moreover, reduced neutrophilia, chemokine release and bacterial exacerbations have been demonstrated. These observations suggest that the drug can down-regulate pulmonary inflammation, even if the precise underlying mechanisms still need to be determined.

Chemokine redundancy in BOS pathogenesis. A possible role also for the CC chemokines: MIP3-beta, MIP3-alpha, MDC and their specific receptors.

Bronchiolitis obliterans syndrome (BOS) is one of the most important factors limiting the long-term survival of lung transplant recipients (LTR), however its pathogenesis still remains unclear. We hypothesized that an increased production of certain specific proinflammatory mediators in the first post-transplant year would predispose to BOS. We retrospectively evaluated temporal kinetics of some CC chemokines that have not yet been evaluated, including CCL3/MIP1-alpha, CCL4/MIP1-beta, CCL17/TARC, CCL19/MIP3-beta, CCL20/MIP3-alpha, CCL22/MDC and CCL26/eotaxin, in broncho-alveolar lavage fluid (BAL-f) in the first post-transplant year in a cohort of 8 LTR before the development of BOS (pre-BOS LTR) and 8 LTR with long-term stable clinical conditions (stable LTR). Chemokine levels were assayed by means of a multiplex sandwich ELISA. Furthermore, for those ligands which resulted significantly predictive of BOS onset, we analyzed the expression of specific receptors (CCR) on BAL cells. The proportion of CCR-expressing BAL cells was assessed by flow cytometry. We demonstrated that MIP3-beta/CCL19, MIP3-alpha/CCL20, MDC/CCL22 levels at 6 months post-transplant significantly predicted BOS onset. In addition, the temporal behavior of these factors resulted significantly different in pre-BOS patients as compared to stable LTR. Finally the expression of CCR was documented on BAL lymphocytes and macrophages, and, in some cases, their expression was found to vary between the two groups. Within the complexity of the chemokine network, these three CCL factors could play an additive role in the pathogenesis of the inflammatory process leading to bronchiolar fibro-obliteration.

Peripheral CD4(+)CD25(+) TREG cell counts and the response to extracorporeal photopheresis in lung transplant recipients.

Extracorporeal photopheresis (ECP) has been proposed as a possible alternative therapy for patients with bronchiolitis obliterans syndrome (BOS), with some evidence of efficacy. Although the mechanism by which ECP exerts its protective effects remains to be determined, two recent studies suggest that the modulation of transplant immune rejection may depend on the capacity to increase the number of peripheral T-regulatory (Treg) cells. We evaluated the effect of ECP treatment on the number of naturally occurring CD4(+)CD25(+) Treg cells in the peripheral blood of six lung transplant recipients: in five cases after failure of augmented or changed immunosuppression for BOS, and in one case owing to persistent acute rejection in a patient who contracted chronic hepatitis C viral infection after lung transplant. A functional stabilization was observed in three of our five patients with BOS, which was accompanied by a slight increase or stabilization of the number of peripheral blood CD4(+)CD25(high) cells with in vitro features of Treg cells. On the contrary, two patients with BOS who did not experience graft functional stabilization also showed a decline in the peripheral Treg subset. In the last patient Treg cell kinetics showed stabilization during the first 5 months of ECP treatment when lung function remained stable and graft histology normalized but showed a subsequent decrease, predating BOS diagnosis. In all, our results indicate that ECP may modulate peripheral Treg cell number but the time course of peripheral Treg cells varies according to graft function.

Peripheral CD4+ CD25+ Treg cell expansion in lung transplant recipients is not affected by calcineurin inhibitors.

CD4+CD25+ regulatory T (Treg) cells have been shown to play a role in allograft tolerance and their peripheral counts vary according to the degree of graft acceptance in lung transplant recipients (LTR). Recent studies demonstrate that certain drugs might modulate generation, expansion and activity of Treg cells. Aim of this study was to evaluate the effect of therapeutic regimens used in our institution on peripheral CD4+CD25(high)CD69- Treg cell numbers in a group of 51 LTR with stable clinical conditions. They were treated with standard immunosuppression: calcineurin inhibitor (CNI)+azathioprine (AZA)+steroids (n=28) or with CNI+mycophenolate mofetil (MMF)+steroids (n=11) or with CNI+steroids (n=12). These stable LTR were compared with age-matched healthy controls (n=35) and with 19 LTR who developed bronchiolitis obliterans syndrome (BOS) and were treated analogously. Stable LTR showed higher peripheral Treg cell counts with respect to age-matched healthy controls (59.9+/-31.8/mul versus 42.1+/-16.9/mul, respectively; p<0.05). This increase was detectable in all patients treated with CNI either in association with AZA or MMF. During these treatments a significant expansion of Treg cell counts was detectable during acute rejection (AR) episodes (86.03+/-26.6/mul during AR versus 36.34+/-7.6 before AR; p<0,05). Moreover, the development of BOS was associated to a significant decrease of Treg cell counts irrespective to the immunosuppressive regimen used. In conclusion, therapeutic regimens based on CNI seem to allow a certain degree of peripheral Treg cell expansion in stable LTR.

Ex vivo evaluation of PPD-specific IFN-gamma or IL-5 secreting cells in the peripheral blood and lungs of patients with tuberculosis.

OBJECTIVES: To evaluate ex vivo purified protein derivative (PPD) specific Th1- and Th2-type functional responses in human tuberculosis (TB). DESIGN: IFN-gamma and IL-5 secreting cells were measured by a computer-assisted ELISPOT assay in the peripheral blood of patients with pulmonary TB, in patients with other respiratory diseases (control patients) and in tuberculin skin test negative or positive healthy controls. Moreover, the number of IFN-gamma or IL-5 spots was assessed in the bronchoalveolar lavage (BAL) cells of five patients with advanced TB and lung inflammation. RESULTS: The frequency of PPD-specific IFN-gamma secreting cells in TB patients was higher than in control patients and healthy subjects. Although the number of PPD-specific IL-5 spots was low, a trend towards a higher frequency was observed in the peripheral blood of TB patients. Patients with advanced TB and lung inflammation had an increased number of both PPD-specific IFN-gamma and IL-5 spots in BAL as compared to that in peripheral blood, but the IFN-gamma/IL-5 ratio was about two-fold lower. CONCLUSIONS: In human TB, the host response in the periphery is driven by a specific Th1-type cytokine response, whereas in the lungs of patients with advanced disease and lung inflammation, polarisation towards a Th2-like bias is observed.

Diazepam-binding inhibitor-derived peptides induce intracellular calcium changes and modulate human neutrophil function.

We studied the effects of two diazepam-binding inhibitor (DBI)-derived peptides, triakontatetraneuropeptide (DBI 17-50, TTN) and eiksoneuropeptide (DBI 51-70, ENP), on cytosolic free Ca2+ concentrations ([Ca2+]i), chemotaxis, superoxide anion (O2-) generation, and phagocytosis in human neutrophils. Both TTN and ENP induced a rapid and transient rise of [Ca2+]i. The effect of TTN depended on the presence of extracellular Ca2+, whereas the effect of ENP also persisted after extracellular Ca2+ chelation. TTN induced neutrophil chemotaxis, stimulated O2- generation, and enhanced phagocytosis. ENP did not affect cell migration and oxidative metabolism but enhanced phagocytosis. Both peptides modulated N-formyl-methionyl-leucyl-phenylalanine- and phorbol myristate acetate-induced O2- generation. Because neutrophils express benzodiazepine receptors of the peripheral type (pBRs) and DBI-derived peptides may interact with such receptors, we investigated the possible role of pBRs in TTN- or ENP-induced effects. The synthetic pBR ligand RO 5-4864 increased [Ca2+]i through extracellular Ca2+ influx and this effect was prevented by the pBR antagonist PK-11195. RO 5-4864, however, was ineffective on neutrophil migration and O2- generation and only slightly affected phagocytosis. Moreover, PK-11195 delayed the [Ca2+]i rise induced by TTN but did not significantly affect its extent, and had no effect on the [Ca2+]i rise induced by ENP. We conclude that DBI-derived peptides induce [Ca2+]i changes and modulate neutrophil function mainly through pBR-independent pathways. In view of the wide cell and tissue distribution of DBI in the brain and in peripheral organs, modulation of neutrophil function by DBI-derived peptides may be relevant for both the neuroimmune network and the development and regulation of the inflammatory processes.

The frequency of interleukin-10- and interleukin-5-secreting CD4+ T cells correlates to tolerance of transplanted lung.

Posttransplant bronchiolitis obliterans syndrome (BOS) results from a chronic immunological/inflammatory insult that leads to fibro-obliteration of the lumen of the allograft airways. The functional T-cell response that is associated with graft acceptance needs to be further clarified in humans. The aim of the present study was to assess the functional activity of peripheral CD4+ T lymphocytes in nine lung transplant recipients with BOS stage II or III (mean 5.4 years after transplant), in seven lung patients with stable clinical conditions (3.4 years posttransplant); and in six normal controls. Peripheral CD4+ T cells, obtained by magnetic bead vs negative purification, were studied using a computer-assisted enzyme-linked immunospot assay (ELISPOT) to assess the number of IFN-gamma-, interleukin (IL)5-, and IL10-gamma-producing cells (no./10(6) CD4+ cells) after allogeneic stimulation. The frequencies of IFN-gamma-producing CD4+ cells did not change significantly in stable patients compared to those with BOS. Interestingly in BOS, the number of IL5- and IL10-producing cells was significantly lower than in stable patients (P < or = .05), suggesting a possible role of these Th2 cytokines in the modulation of graft tolerance.

Influence of ceftriaxone on natural defense systems.

The in vitro and in vivo effects of ceftriaxone, a newly developed cephalosporin, on phagocytes and T-cell subsets were studied. Ceftriaxone in vitro did not interfere with phagocytosis, phagocytosis-dependent metabolic activation, and microbicidal activity (against Staphylococcus aureus and Candida albicans) of human neutrophils at doses ranging from 10 to 320 micrograms/ml. In vitro chemotaxis was markedly inhibited both in the presence of and after 30 minutes of exposure to 40 micrograms/ml of ceftriaxone. Six normal adult volunteers were given 2 g of antibiotic intravenously every 24 hours for six days. The in vivo effects of ceftriaxone on neutrophil functions and T-cell subsets were investigated before and 30 minutes after injection on the first and third days. No change in any phagocyte function (chemotaxis, phagocytosis, phagocytosis-dependent metabolic activation, and microbicidal activity) or in the distribution of T-cell subpopulations was observed.

The assessment of IFN-gamma and its regulatory cytokines in the plasma and bronchoalveolar lavage fluid of patients with active pulmonary tuberculosis.

OBJECTIVES: To assess the role of IFN-gamma and its regulatory cytokines in active pulmonary tuberculosis (TB). DESIGN: Cytokines were measured in the plasma of TB patients and healthy subjects with different risk for TB exposure. In addition, cytokine profile was assessed in the bronchoalveolar lavage fluid (BALf) of six TB patients and nine normal controls. RESULTS: Circulating IFN-gamma, IL-10 and IL-18 were higher in TB patients than in control groups. Plasma IL-12 levels were extremely variable, and no difference was observed among study groups. An inverse correlation between plasma IFN-gamma and IL-10 levels was found in TB patients. Furthermore, circulating IL-18 correlated with IL-10 but not with IFN-gamma levels. Finally, IFN-gamma, IL-18 and IL-12 were increased in the BALf of TB patients, whereas no difference was observed in IL-10 levels. CONCLUSIONS: In human TB, at least at certain disease stages, there is a differential compartmentalization of the IFN-gamma-regulatory factors IL-12 and IL-10, the former being concentrated in the lungs and the latter being present in peripheral circulation. In addition, our findings address more critically the role of IL-18 in the host response to tuberculosis infection in humans.

Assessment of lymphocyte subsets and neutrophil leukocyte function in chronic psychiatric patients on long-term drug therapy.

1. Lymphocyte subsets and neutrophil function were studied in chronic psychiatric patients on long-term multiple drug therapy, and the correlation with disease and drug treatments was also investigated. 2. Patients showed decreased CD4+ percentage, CD4+/CD8+ ratio, B lymphocyte percentage, increased absolute and percentage NK, and impaired neutrophil chemotaxis, phagocytosis, and oxidative metabolism. Correlations were found between: patient status and lower CD4+ percentage, CD4+/CD8+ ratio, neutrophil chemotaxis, phagocytosis, and oxidative metabolism; schizophrenia and higher absolute and percentage NK, and neutrophil random migration; benzodiazepines and higher CD8+ absolute number and lower NBT reduction frequency; carbamazepine and higher NK percentage, neutrophil chemotaxis, phagocytosis, stimulated O2-production, and lower microbicidal activity. 3. The present study provides direct evidence for the existence of immunologic abnormalities in a population of chronic psychiatric patients on long-term drug therapy. Although a possible role by other factors could not be excluded, such abnormalities are strongly associated with chronic administration of benzodiazepines and carbamazepine. Further investigations are warranted to confirm these findings and disclose the possible mechanism(s) involved.

The effect of teicoplanin on leukocytic activity and intraleukocytic micro-organisms.

The interference of teicoplanin with certain phagocyte activities was investigated in comparison with that of vancomycin. Neither teicoplanin nor vancomycin interfered with chemotaxis, adherence, phagocytosis or nitroblue tetrazolium reduction of human neutrophils. Teicoplanin, but not vancomycin, enhanced intracellular killing by neutrophils from normal donors and from a patient with chronic granulomatous disease. Human monocytes in the absence of fresh human serum did not significantly kill Staphylococcus aureus but when pre-treated with teicoplanin 90% of phagocytozed bacteria were killed during 4 h incubation.

Antibiotics and their interaction with the host defense system in vivo.

The Authors review their own data on the in-vitro effect of a wide number of chemotherapeutic agents on phagocyte functions (chemotaxis, phagocytosis, phagocytosis-dependent metabolic activation, microbicidal activity). Aminoglycosides affected some leukocyte functions only at concentrations higher than those achieved in therapy. Macrolides, glycopeptides and fluoroquinolones showed no toxic effect on phagocytic activities. Beta-lactams, generally, did not influence phagocytic activities. However, ceftriaxone and cefoperazone irreversibly inhibited neutrophil chemotaxis. Cefodizime, on the other hand, enhanced phagocytosis of both neutrophils and monocytes, when non-opsonized particles were used as phagocytic challenge. Rifamycins inhibited neutrophil chemotaxis and enhanced the intracellular killing of S. aureus. These interactions with phagocyte function were tested ex vivo on cells of normal volunteers treated with these antibiotics. While no effect on chemotaxis in subjects treated with ceftriaxone and cefoperazone could be demonstrated, both cefodizime and rifampicin maintained their in-vitro activity in ex-vivo experiences. These findings seem to indicate that, so far, no definite conclusion can be drawn on the in-vivo significance of in-vitro findings.

Effects of continuous or pulsed exposure to rifabutin and sparfloxacin on the intracellular growth of Staphylococcus aureus and Mycobacterium tuberculosis.

The time-kinetics of the intracellular bioactivity and intracellular post-antibiotic effect (PAE) of rifabutin and sparfloxacin against Staphylococcus aureus and Mycobacterium tuberculosis, grown in human monocytes, were evaluated. Intracellular bactericidal activity against staphylococci was shown in the presence of extracellular drug concentrations equal or superior to 1/10 plasma Cmax. The bactericidal activity of rifabutin was dependent on both its extracellular concentrations and the exposure time. In contrast, the pattern of the intracellular activity of sparfloxacin was characterized by a minimal concentration dependent killing. Both antibiotics (from 1/10 to the expected lung Cmax) showed intracellular bioactivity against M. tuberculosis H37Ra and H37Rv strains. A long intracellular PAE on staphylococci (>4 hours) was demonstrated when drugs were removed from the infected monocytes after 1 h treatment. Our findings suggest that rifabutin and sparfloxacin may be useful in the treatment of lower respiratory tract infections due to intracellular pathogens.

Inhibition of intracellular growth of Staphylococcus aureus by exposure of infected human monocytes to clarithromycin and azithromycin.

The direct effect of clarithromycin and azithromycin on human polymorphonuclear leukocyte (PMN) functions and their intracellular activity against Staphylococcus aureus, phagocytosed by human monocytes, were studied. The presence of both antibiotics, in the range of concentrations from 0.25 to 20 micrograms/ml, did not affect chemotaxis, opsonized-zymosan phagocytosis, respiratory burst measured by nitroblue tetrazolium reduction and phorbol myristate acetate-induced superoxide production, or the microbicidal activity of human PMNs against Candida albicans. Both macrolides were bactericidal against staphylococci in the monocyte system, while bacteriostatic activity was found in cell free system. At concentrations equal to the minimum inhibitory concentrations (MICs) (0.75 and 0.1 respectively for azithromycin and clarithromycin) more than 99% of intraphagocytic S. aureus were killed after 24 h incubation. Increasing the concentrations of each drug above the MICs (5 and 10 MICs) did not alter the killing rate of intracellular bacteria. Moreover, no differences between the intracellular bioactivity of these antibiotics were demonstrated, despite their different uptake kinetics.

Requirements for intracellular accumulation and release of clarithromycin and azithromycin by human phagocytes.

Determination of clarithromycin (CL) and azithromycin (AZ) uptake by human polymorphonuclear leukocytes (PMNs), monocytes and alveolar macrophages showed that AZ achieved higher levels than CL. The uptake kinetics of AZ were time-dependent over an 18 h period, while those of CL were similar to erythromycin (ER) kinetics, with a maximum level of incorporation being obtained after a 60 min incubation. The accumulation of both drugs was influenced by extracellular antibiotic-concentrations, PMN viability, extracellular calcium, physiological environmental temperature and pH. The uptake was not modified by inhibitors of cell metabolism or activators of cell membranes. After removal of extracellular antibiotic, the release of AZ from PMNs was very slow: nearly 50% of the drug remained cell-associated after 24 h incubation. The efflux of this derivative was significantly enhanced when drug-loaded PMNs were stimulated by phorbol-myristate acetate (PMA). The kinetics of CL release indicated that this macrolide behaved like ER. Nevertheless, about 10% of the initial cell-associated antibiotic showed a prolonged retention. On the whole, these data suggest that diffusion through cell membranes and trapping into acidic compartments of PMNs are important events in CL and AZ uptake.

A survey of antimicrobial drug resistance in respiratory tract pathogens, isolated in a northern Italian teaching hospital between 1990 and 1999.

Drug susceptibility test results of respiratory tract pathogens, isolated from patients admitted to the Clinic of Respiratory Diseases of the IRCCS San Matteo Hospital, University of Pavia (Italy) between 1990 and 1999, were retrospectively evaluated. A total of 1366 bacterial isolates were collected, including 499 gram-positive and 867 gram-negative strains. In comparison to methicillin-susceptible Staphylococcus aureus, the methicillin-resistant strains (MRSA) showed high levels of resistance to many selected antibiotics, except for glycopeptides. Resistance rates to beta-lactams were high in both Pseudomonas aeruginosa and in the other gram-negative isolates, while aminoglycoside and ciprofloxacin resistance was less than 20%. Some pathogens became more resistant to selected antimicrobials during the observation period, including staphylococci to methicillin, MRSA to ciprofloxacin, P. aeruginosa isolates to imipenem and ciprofloxacin, and the other gram-negative strains to almost all drugs considered, with the exception of cefotaxime and cotrimoxazole.

Acute Chlamydia pneumoniae and Mycoplasma pneumoniae infections in community-acquired pneumonia and exacerbations of COPD or asthma: therapeutic considerations.

Rates of acute Chlamydia pneumoniae and Mycoplasma pneumoniae infections were determined in 115 adults hospitalized for community-acquired pneumonia (CAP), purulent exacerbations of COPD and acute exacerbations of bronchial asthma, by means of serology and molecular methods. Results were compared with those obtained in a matched control group. Common respiratory pathogens were isolated by cultures in 22.5% and 22.2% of CAP and exacerbated COPD patients, respectively. Cultures from exacerbated asthma patients were always negative. Serological and molecular evidence of current C. pneumoniae infection was obtained in 10.0%, 8.9% and 3.3% of CAP, COPD and asthma cases. The corresponding rates of acute M. pneumoniae infection were 17.5%, 6.7% and 3.3%, respectively. Finally, no difference was found between typical and atypical pathogen rates. These findings highlight the importance of taking into account C. pneumoniae and M. pneumoniae infections in guiding the choice of empirical antibacterial treatment for CAP and purulent exacerbations of COPD.

A 10-year survey of Mycobacterium tuberculosis isolates in Pavia and their drug resistance: a comparison with other Italian reports.

A retrospective review was made of the bacteriological and medical records of patients with culture-confirmed pulmonary tuberculosis who attended the IRCCS San Matteo Polyclinic of Pavia, between 1990 and 2000. Altogether, 279 patients were included in the survey: 220 new cases and 59 prior treatment cases. Resistance to at least one drug, and resistance to both isoniazid and rifampicin (MDR) were more common among previously treated patients than among new cases (86.4% vs. 34.1%, and 44% vs. 5.9%, respectively). While the frequency of resistance to any drug showed no variation in the period examined, a trend toward a progressive decrease in the frequency of primary MDR-TB was observed (from 11.9% in 1990-1992 to 1.3% in 1998-2000). The level of resistance observed in our study suggests that all isolates of Mycobacterium tuberculosis should be tested for drug susceptibility, especially when obtained from patients who report a previous episode of the disease.

Monocyte chemoattractant protein-1 levels in bronchoalveolar lavage fluid of lung-transplanted patients treated with tacrolimus as rescue treatment for refractory acute rejection.

BACKGROUND: Cytokines are important mediators of the complex process of extravasation and influx of peripheral mononuclear cells into a site of graft injury, an action that may be affected by the immunosuppressive regimen. The aim of this study was to compare the effect of different immunosuppressive regimens on cytokine expression in the grafted lung. METHODS: We analyzed the cytokine profiles in broncho-alveolar lavage fluid (BAL-F) from 18 lung transplanted patients undergoing a shift from a cyclosporine- to a tacrolimus-based triple therapy regimen due to refractory acute rejection. RESULTS: Three months after the conversion to tacrolimus, BAL-F levels of interleukin 8 (IL8), IL18, IL12 and IL10 were not significantly different than those measured before conversion. In contrast, monocyte chemoattractant protein-1 (MCP-1) levels showed a significant and sustained decrease in BAL-F during tacrolimus therapy. In addition the levels of gamma interferon (IFN-gamma) in the BAL-F were decreased albeit not significantly. CONCLUSIONS: These findings suggest that the clinical and functional stabilization of patients observed after conversion to a tacrolimus based regimen, may be due, at least in part, to the induced down-regulation of MCP-1 production.