Oral octreotide capsules for the treatment of acromegaly: comparison of 2 phase 3 trial results.

PURPOSE: Results are presented from 2 to 3 trials investigating oral octreotide capsules (OOC) as an alternative to injectable somatostatin receptor ligands (iSRLs) in the treatment of acromegaly. METHODS: CH-ACM-01 was an open-label trial (N = 155) and CHIASMA OPTIMAL was a double-blind placebo-controlled (DPC) trial (N = 56), both investigating OOC as maintenance therapy for patients with acromegaly who were biochemical responders receiving iSRLs. RESULTS: Baseline characteristics in both trials reflected those expected of patients with acromegaly responding to treatment and were similar between trials, despite differences in inclusion criteria. OOC demonstrated a consistent degree of biochemical response across trials, with 65% of patients in CH-ACM-01 maintaining response during the core period and 64% of patients in CHIASMA OPTIMAL at the end of the DPC. Mean insulin-like growth factor I (IGF-I) levels remained within inclusion criteria at the end of treatment in both trials. Of 110 patients entering the fixed-dose phase in CH-ACM-01, 80% maintained or improved acromegaly symptoms from baseline to the end of treatment. Over 85% of patients in both trials elected to continue into the extension phases. OOC were found to be well tolerated across both trials, and no dose-related adverse events were observed. CONCLUSIONS: OOC demonstrated remarkably consistent results for biochemical response, durability of response, and preference to continue with oral treatment across these 2 complementary landmark phase 3 trials, despite differences in the design of each. Trial registration NCT03252353 (August 2017), NCT01412424 (August 2011).

Effect of systemic steroid therapy in Graves' orbitopathy on regulatory T cells and Th17/Treg ratio.

PURPOSE: Glucocorticoids are a mainstay treatment for Graves' orbitopathy, yet their exact mechanisms of action remain unclear. We aimed to determine whether the therapeutic effects of systemic steroid therapy in Graves' orbitopathy are mediated by changes in regulatory T lymphocytes (Tregs) and T helper 17 lymphocytes (Th17). METHODS: We assessed Treg and Th17 levels in the peripheral blood of 32 patients with active, moderate-to-severe Graves' orbitopathy who received 12 weekly pulses of methylprednisolone, and determined their association with disease severity, disease activity, and treatment outcomes. The acute orbitopathy phase was confirmed based on clinical evaluation and magnetic resonance imaging, and assessed using the clinical activity score (CAS). The severity of the disease was classified according to ETA/EUGOGO guidelines, and quantified based on the total eye score. Treatment response was determined based on specific criteria (e.g., changes in CAS score, diplopia grade, visual acuity, etc.). Treg and Th17 cells were identified using flow cytometry. RESULTS: Methylprednisolone treatment improved the activity of the disease and altered the Th17/Treg balance (i.e., the percentage of Tregs decreased while the number of Th17 cells remained unchanged). There was no association between the Treg/Th17 ratio and the activity and severity of the disease or the treatment response. CONCLUSIONS: Therapeutic effects of steroid therapy in Graves' orbitopathy are not mediated by Treg and Th17 alterations in the peripheral blood. The decrease in peripheral Treg percentage is likely a consequence of the non-specific effects of steroids and does not impact clinical outcome.

CARDIOVASCULAR COMPLICATIONS OF ACROMEGALY.

Acromegaly is associated with increased mortality and decreased life expectancy. Cardiovascular disease is the principal cause of premature mortality in patients with acromegaly, accounting for about 60% of deaths. GH and/or IGF-I exert direct cardiac effects: enhance cardiac contractility, stimulate cardiomyocyte growth, influence calcium influx in cardiomyocytes. Cardiac remodelling is influenced by hypertension and insulin resistance. Among cardiovascular risk factors arterial hypertension, reported in 35% of patients with acromegaly, ranks among most important negative prognostic factors for mortality. Hypertension plays significant role in the development of cardiac hypertrophy, especially in older acromegalic patients and diastolic blood pressure is best predictive factor for cardiac hypertrophy. Therefore, early and aggressive hypertension treatment is essential for prognosis in acromegaly. Other important risk factors are: valvular defects, arrhythmias, endothelial dysfunction, heart failure, lipid abnormalities and coronary artery disease. Numerous studies suggest that patients with acromegaly are under threat of arrhythmias, especially those with structural heart abnormalities. Congestive heart failure as end-stage acromegalic cardiomyopathy occurs usually in older patients, with long-term uncontrolled disease and other cardiovascular and metabolic complications. Relation between acromegaly and coronary artery disease is controversial as it seems to be connected rather with classical cardiovascular risk factors than GH and IGF-1 overexpresion.

Growth Hormone Treatment Increases Plasma Irisin Concentration in Patients with Turner Syndrome.

Irisin (Ir) deficiency may be a contributing factor in metabolic disease. This study aimed to investigate the effect of supraphysiological doses of recombinant human growth hormone (rhGH) on Ir plasma concentration in relation to metabolic disorders, including obesity and other components of metabolic syndrome. We studied 36 girls with Turner syndrome (mean age 8.2 years) treated with rhGH (0.05 mg/kg/day). Anthropometric data and fasting blood levels [e. g., Ir, insulin, glucose, glycated hemoglobin (HbA1c), IGF-1, IGFBP-3, cholesterol, insulin resistance (HOMA-IR), and ß-cell function (HOMA-ß)] were analyzed prior to and following rhGH therapy [mean (SD) follow-up of 1.47 (0.89) years]. Insulin sensitivity (Matsuda index) was calculated before and after the glucose load. Following rhGH therapy, an increase in IGF-1 [mean (SD) of 119.40 (62.47) ng/ml to 439.08 (209.91) ng/ml, p=0.000], Ir [2.10 (1.03) µg/ml to 2.48 (0.78) µg/ml, p=0.036], HOMA-IR [median (IQR) of 0.64 (0.45-1.30) to 0.92 (0.67-2.36), p=0.0206], and HOMA-ß values [45.00 (27.69-72.00) to 81.53 (51.43-132.00), p=0.0447] were observed. Multiple regression analysis yielded no associations between Ir and metabolic and hormonal parameters before rhGH treatment; however, on rhGH, the model (R2=0.56, adjusted R2=0.45) showed positive associations between Ir and IGF-1 standard deviation score and HbA1c, and negative associations between Ir and fasting blood glucose, HDL-cholesterol, and triglycerides. Despite manifestation of insulin resistance, rhGH application had a positive effect on Ir regulation, and restored physiological conditions of lipid and glucose metabolism.

Diabetes and Cancer: a Review of Current Knowledge.

Diabetes mellitus (DM), one of the most common life-threatening illnesses worldwide, is a group of metabolic diseases, characterized by sustained hyperglycemia. The global prevalence of diabetes mellitus among adults reached 387 millions in 2014 and is still rising. It is suggested there is a strong association between diabetes mellitus (especially type 2 diabetes mellitus) and carcinogenesis. The possible biological links between diabetes mellitus and cancer comprise hyperinsulinemia, hyperglycemia and fat-induced chronic inflammation. Although, the strongest association refers to pancreas and liver, there are many other organs involved in carcinogenesis in diabetic patients including breast, endometrium, bladder and kidney.Recent studies suggest that there is also association between cancer incidence and anti-diabetic medications. It was observed that some medications decrease the risk of carcinogenesis and some increase that risk. The majority of studies concern metformin, a drug of choice in type 2 diabetes mellitus, and its anti-neoplastic and tumor-suppressing activity. The positive effect of metformin was found in numerous researches investigating breast, pancreas, liver, colon, ovaries and prostate tumors.Because a variety of studies have suggested that diabetes mellitus and cancer are frequently coexisting diseases, recently published studies try to explain the influence of diabetes mellitus and anti-diabetic medications on carcinogenesis in different organs.We present the review of the latest studies investigating the association between both diabetes mellitus and anti-diabetic medications and cancer incidence and prognosis.Particularly we highlight the problem of concomitant head and neck cancers in diabetics, rarely analysed and often omitted in studies.

Effective therapy of insulinoma by using long-acting somatostatin analogue. A case report and literature review.

We are reporting a case of 68-year-old woman with insulinoma, after a non-successful tumor surgery and a long-term diazoxide treatment. She had a lot of hypoglycemia cases, and a weight gain of 50 kg. An abdominal CT scan demonstrated a tumor 28 mm in the diameter, in the head of the pancreas. The patient did not agree for the repeated insulinoma surgery. Furthermore, we found a lesion in the left adrenal gland (14 mm in the diameter) and in the right lung (8 mm in the diameter). Pheochromocytoma was diagnosed on the basis of hypertension, elevated levels of normetanephrine in the 24-h urine collection, and an elevated level of norepinephrine in a plasma sample. After the left adrenal gland removal we observed lower blood pressure. Since we had revealed the presence of somatostatin receptors by the somatostatin receptors scintigraphy, we decided to control hypoglycemia by a monthly subcutaneous administration of the long-acting lanreotide. Because of higher glucose levels (300-400 mg/dl) we started an intense insulin therapy. Nowadays, the patient feels better, she has lost 20 kg of her body weight, and we have observed normal blood glucose levels during the long-term lanreotide treatment. We have noticed neither side effects nor hypoglycemic episodes and we have reduced the dose of insulin. The presented case can be an evidence of the effective treatment of the pancreatic neuroendocrine tumor of insulinoma type, with somatostatin analogue.

Turner's syndrome followed by acromegaly in the third decade of life: an unusual coincidence of two rare conditions.

We present an unusual coincidence of acromegaly and Turner's syndrome. A girl was diagnosed with Turner's syndrome when she presented with short stature, primary amenorrhea, Hashimoto's thyroiditis, and some heart and renal anomalies. No therapy with growth hormone and only a few months treatment with estrogen-progestin was given. A typical picture of acromegaly occurred in the third decade of her life. Bone radiographs and densitometry suggested the more pronounced influence of acromegaly within the skeleton, but no features typical for acromegaly were found in the cardiovascular system. To our knowledge no case of coincidence of the above mentioned conditions has been reported to date. The influence of both of these conditions on bones and heart is discussed.

Acromegaly due to GHRH-secreting large bronchial carcinoid. Complete recovery following tumor surgery.

A case of acromegaly, secondary to GHRH secretion by a large bronchial carcinoid is reported. A 61-year-old woman presented with typical symptoms and signs of acromegaly for at least 10 years. She suffered from recurrent pneumonias, but repeated chest X-ray examinations failed to demonstrate the bronchial tumor. The diagnosis was confirmed by elevated GH, IGF-1 and GHRH secretion. We have shown an enlarged pituitary gland without focal lesions together with a cerebral meningioma on MRI and the presence of a bronchial carcinoid tumor. The latter was confirmed by histology carried out after bronchoscopy and tumor excision. We observed partial suppression of GH secretion following short-term oral bromocriptine administration in this patient. Surgical removal of the carcinoid tumor resulted in a complete clinical, hormonal and radiological cure of acromegaly. This case of acromegaly due to ectopic GHRH secretion by bronchial carcinoid differs from others described in the literature by an atypical large tumor size, the suppression of elevated GH secretion by oral bromocriptine and a concomitant meningioma.

Quantitative ultrasound of the heel and some parameters of bone turnover in patients with acromegaly.

Acromegaly caused by growth hormone (GH) hypersecretion is characterized by enhanced skeletal growth and soft tissue enlargement. Insulin-like growth factor-1 (IGF-1) is the main peripheral mediator of GH action and it has a crucial role in the maintenance of a normal bone mass. However, in some patients with acromegaly, secondary osteoporosis is observed, despite the strong anabolic effect of GH and IGF-1 in bones. It is thought to be due to hypogonadism. The bone changes are accompanied by increased turnover. The aim of this study was to assess bone properties by ultrasound and turnover in patients with acromegaly. The study was carried out in 26 patients (13 men, 13 women): 14 with active acromegaly and 12 cured by surgery who had non-active disease. Speed of sound (SOS), broadband ultrasound attenuation (BUA) and their combination Stiffness Index (SI) by quantitative ultrasound (QUS) of the heel, hormonal status, serum osteocalcin (OC) concentration and the urinary excretion of pyridinoline collagen crosslinks (PYR) were all studied. Controls were 20 age- and sex-matched healthy persons. We observed statistically significantly lower QUS values in patients with active disease than in those whose disease was cured. The differences were more pronounced in men. QUS values were lower in the entire group of patients compared with the controls; however, the differences were not statistically significant. Serum OC concentrations and urinary PYR excretion were higher in active disease. Statistically significant inverse correlations between serum GH levels and SOS (r = -0.58, p = 0.002); BUA (r = -0.66; p = 0.0001); T-score (r = -0,65, p = 0.0001) and Z-score (r = -0.66, p = 0.0001) were found only in male patients. No correlations between IGF-1, duration of the disease, OC, PYR and other data studied were observed. In conclusion, we have shown decreased QUS parameters suggesting impaired bone properties and quality in terms of density and elasticity in men, but not in women, with active acromegaly. This finding suggests osteoporosis with increased bone turnover. The above-mentioned changes might be caused by the action of GH on trabecular bone and its metabolism, since no hypogonadism in male patients was shown. Moreover, the influence of acromegaly on heel geometry and soft tissue swelling should also be considered.

Assessment of human body composition using dual-energy x-ray absorptiometry and bioelectrical impedance analysis.

BACKGROUND: Human body composition, particularly the content of fat tissue and its distribution, has been extensively measured in healthy, diseased, obese and elderly subjects. A variety of non-invasive methods have been applied for these studies. Bioelectrical impedance analysis (BIA) is a commonly used method, based on the conduction of electrical current in the body and the differences in the ability to conduct electricity between the fat and water components of the body. Recently, dual-energy x-ray absorptiometry (DEXA) has been introduced for bone mass, bone mineral density and body composition studies. Unlike other methods, DEXA measures three components of the body: bone mineral content, fat tissue mass, and lean tissue mass, and additionally regional fat distribution. The objective of this study was to compare body composition as assessed by DEXA and BIA methods in a sample of 100 patients. MATERIAL AND METHODS: Body composition was studied in 100 consecutive subjects, 59 women and 41 men. The lean body mass (LBM), fat body mass (FBM), and percent body fat (%BF) were measured by the DEXA and BIA techniques. RESULTS: There were highly statistically significant linear relationships between LBM, FBM and %BF assessed by DEXA and BIA in both sexes (p<0.001 for all measurements). No influence of age or BMI on the relationship between DEXA and BIA results was observed. Differences were observed between DEXA and BIA measurements of both fat and fat-free tissue. The results suggest that DEXA may underestimate the LBM and overestimate body fat compared with BIA, probably due to different assumptions about the constants. CONCLUSIONS: We conclude that both methods are suitable for body composition studies.

Axial bone mineral density in patients with acromegaly.

RATIONALE AND OBJECTIVES: The purpose of this study was to assess the influence of long-term elevated levels of growth hormone and insulin-like growth factor I on bone mineral density (BMD) of the spine in patients with acromegaly. MATERIALS AND METHODS: The spinal BMD in 40 patients with acromegaly was measured with quantitative computed tomography. The result was expressed as the mean of six measurements of consecutive vertebral bodies and as a z score. Twenty age- and sex-matched healthy persons also underwent spinal BMD measurement and served as controls. RESULTS: In 36 of the 40 patients, the BMD z score ranged within 2 standard deviations (SDs) above or below the mean. Only two patients (one man and one woman) had enhanced BMD loss (below 2 SD). Two other female patients had BMD values of more than 2 SD above the mean. Differences between patient subgroups were not statistically significant, but a statistically significant (P < .05) positive correlation was found between basal serum concentration of growth hormone and spinal BMD for the entire patient group. No correlation between BMD and basal serum concentration of insulin-like growth factor I was found. CONCLUSION: Hypersecretion of growth hormone in patients with acromegaly, regardless of other factors, has no evident effect on BMD of the lumbar spine.

[Bone densitometry: interpretation of a single measurement]. / Osteodensytometria--interpretacja wyniku pojedynczego badania.

The use of bone densitometry in clinical practice is wide, since it is very useful to confirm osteoporosis, predict a fracture or monitor the treatment. In some cases the result of a single, sometimes by chance densitometry can provide a false conclusion and therapeutic decision when interpreted without sufficient knowledge of an individual clinical picture and methodological conditions. A number of densitometric analyses were carried out in healthy male showing a considerable dispersion in the results. Especially methods used in screening studies (SPA, SXA, QUS) provided results lower in contrast to results obtained by standard methods (DEXA, QCT). It suggests to be very careful when interpreted the result of a single densitometry without personal contact with patient and his history, or without sufficient knowledge of densitometric methods.

[The influence of thyrotoxicosis and thyroxine therapy on the risk of osteoporosis]. / Wplyw nadczynnosci tarczycy i leczenia tyroksyna na zagrozenie osteoporoza.

The review presents data from literature on the influence of endogenous and exogenous thyroid hormones on the activity of bone resorption and formation followed by enhanced bone loss and risk of osteoporosis. Thyroid hormones represent commonly prescribed medicines, often are used without control of their effects, especially in older patients at risk of fractures due to osteoporosis. The fracture risk increases in cases of untreated thyrotoxicosis, when administered suppressive doses of thyroxine, in postmenopausal women and patients with low peak bone mass. Fractures are more likely in parts of skeleton with cortical bone predominance e.g. distal forearm and hip.

Matrix metalloproteinases generate angiostatin: effects on neovascularization.

Angiostatin, a cleavage product of plasminogen, has been shown to inhibit endothelial cell proliferation and metastatic tumor cell growth. Recently, the production of angiostatin has been correlated with tumor-associated macrophage production of elastolytic metalloproteinases in a murine model of Lewis lung cell carcinoma. In this report we demonstrate that purified murine and human matrix metalloproteinases generate biologically functional angiostatin from plasminogen. Macrophage elastase (MMP-12 or MME) proved to be the most efficient angiostatin-producing MMP. MME was followed by gelatinases and then the stomelysins in catalytic efficiency; interstitial collagenases had little capacity to generate angiostatin. Both recombinant angiostatin and angiostatin generated from recombinant MME-treated plasminogen inhibited human microvascular endothelial cell proliferation and differentiation in vitro. Finally, employing macrophages isolated from MME-deficient mice and their wild-type littermates, we demonstrate that MME is required for the generation of angiostatin that inhibits the proliferation of human microvascular endothelial cells.

Tumor necrosis factor alpha-induced eosinophil accumulation in rat skin is dependent on alpha4 integrin/vascular cell adhesion molecule-1 adhesion pathways.

Tumor necrosis factor alpha (TNFalpha) is a cytokine implicated in the pathogenesis of numerous chronic and acute inflammatory conditions. In the present study, we have characterized the ability of TNFalpha in inducing eosinophil accumulation in rat skin and have shown the inhibitory effects of anti-alpha4 integrin and anti-vascular cell adhesion molecule-1 (VCAM-1) antibodies on this response. The intradermal injection of recombinant human TNFalpha induced a slowly developing, dose-dependent accumulation of 111In-eosinophils in rat skin that was maximal at the dose of 10(-11) mol/site. Coadministration of TNFalpha with the soluble TNFalpha receptor (p55)-IgG fusion protein (TNFR-IgG) totally inhibited the 111In-eosinophil accumulation induced by the cytokine. The TNFalpha-induced 111In-eosinophil accumulation was not affected after pretreatment of rats with the platelet-activating factor (PAF) receptor antagonist UK-74,505 or the antihuman interleukin-8 monoclonal antibody (MoAb) DM/C7. In contrast, the intravenous administration of an anti-alpha4 integrin MoAb, HP2/1 (3.5 mg/kg), or an anti-VCAM-1 MoAb, 5F10 (2 mg/kg), greatly inhibited the 111In-eosinophil accumulation induced by TNFalpha (the responses detected at 10(-11) mol/site were inhibited by 78% and 50%, respectively). These results show that TNFalpha is an effective inducer of eosinophil accumulation in vivo, with this response being dependent on an interaction between alpha4 integrins and VCAM-1.

Role of interleukin 8 on leucocyte-endothelial cell adhesion in intestinal inflammation.

BACKGROUND: An important action of interleukin 8 (IL8) is stimulation of granulocytes. The object of this study was to assess the contribution of IL8 to the leucocyte-endothelial cell interactions associated with intestinal inflammation in the rat. METHODS: Two indomethacin injections (48 and 24 hours prior to the experiments) induced a longlasting ileitis in rats. The number of adherent and emigrated leucocytes, leucocyte rolling velocity, and shear rate were monitored in normal and inflamed mesenteric postcapillary venules. Some animals received a monoclonal antibody (MAb) against IL8 or CD11b/CD18 at 24 and 12 hours prior to the experiment. RESULTS: Indomethacin elicited a seven-fold increase in leucocyte adherence and a 5.4-fold increase in leucocyte emigration, while leucocyte rolling velocity was reduced by nearly 80%. The indomethacin induced increases in leucocyte adherence and emigration were significantly reduced (by 57% and 67%, respectively) while leucocyte rolling velocity was increased (to 63% of control) by the IL8-specific MAb. The level of inhibition seen with the IL8 MAb was similar to that associated with administration of a MAb directed against the leucocyte adhesion molecule CD11b/CD18. CONCLUSIONS: IL8 contributes to the leucocyte-endothelial cell interactions elicited in mesenteric venules by indomethacin.

Identification and characterization of rhesus macaque interleukin-8.

To establish a direct link between IL-8 and inflammation in vivo, we first isolated the gene encoding rhesus macaque IL-8. The open reading frame directs the translation of a 101 amino acid (aa) precursor, which is 94% identical to human IL-8. Rhesus IL-8 was expressed in bacteria and purified to homogeneity with ion-exchange chromatography. Pure rhesus IL-8 was biologically active as measured by its ability to bind specifically to either rhesus (Kd = 0.5 nM) or human (Kd = 2 nM) IL-8 receptors and to promote in vitro chemotaxis of rhesus (EC50 = 2 nM) or human neutrophils (EC50 = 4 nM). Moreover, a mouse monoclonal antibody, DM/C7, which neutralizes human IL-8 activity, also recognized and neutralized (IC50 = 0.5-3.0 microgram/ml) rhesus IL-8 in vitro. Systemic administration of DM/C7 completely inhibited the dermal inflammation of rhesus ears induced by the external application of phorbol myristoyl acetate. These observations reveal that rhesus IL-8 is structurally and functionally similar to human IL-8 and suggests that IL-8 plays a prominent role in a primate model of inflammation.

IL-1 is a potent inducer of eosinophil accumulation in rat skin. Inhibition of response by a platelet-activating factor antagonist and an anti-human IL-8 antibody.

The aim of the present study was to investigate directly and characterize the ability of IL-1 beta in inducing eosinophil accumulation in vivo. For this purpose, we studied the recruitment of 111In-labeled eosinophils in rat skin in response to intradermally injected rat rIL-1 beta. Rat rIL-1 induced a dose-dependent accumulation of 111In-labeled eosinophils, with the maximal response being detected at 5 x 10(-13) mol/site. This response was slow in onset, progressively increasing over the 4-h period investigated. Rat rIL-1 also induced a small level of edema, as measured by the local accumulation of i.v. 125I-labeled albumin, which developed with a time course similar to that of 111In-labeled eosinophil accumulation. Co-administration of the cytokine with the IL-1R antagonist, IL-1ra, or actinomycin D, significantly inhibited the 111In-labeled eosinophil accumulation, and reduced the edema formation, induced by rat rIL-1. In addition, the 111In-labeled eosinophil accumulation was significantly suppressed in animals treated with the PAF antagonist UK-74,505 or an anti-human IL-8 mAb DM/C7. These observations demonstrate for the first time that IL-1 beta is a potent inducer of eosinophil accumulation in vivo. Moreover, the results reveal that this activity of IL-1 beta is receptor mediated and dependent on the induction of proteins that may be involved in the local generation of secondary inflammatory mediators including PAF and an IL-8-like molecule. These findings are consistent with the view that endogenously generated IL-1 may play an important role in the recruitment of eosinophils at sites of allergic inflammation.

Interleukin 8 and mast cell-generated tumor necrosis factor-alpha in neutrophil recruitment.

In the reverse passive Arthus reaction in mouse skin and immune injury of mouse dermal basement membrane, neutrophil (PMN) infiltration in mast cell deficient WBB6F1-W/Wv (W/Wv) mice was only 40% of that in WBB6F1-(+)/+ (+/+) mice that had a normal mast cell repertoire. An anti-tumor necrosis factor-alpha (TNF-alpha) monoclonal antibody (mAb) decreased PMN infiltration by 35-80% in +/+ but not W/Wv mice. In addition, an anti-human interleukin-8 (IL-8) MAb, DM/C7, inhibited PMN infiltration of the skin induced by either intradermal administration of recombinant human IL-1 beta or immune complex deposition. In both models of immune complex injury, DM/C7 reduced PMN infiltration by 40-60% in +/+ mice but not W/Wv mice. PMN infiltration and the sensitivity of this infiltration to anti-TNF-alpha or DM/C7 MAb in W/Wv mice whose mast cell population had been restored was indistinguishable from the influx observed in +/+ mice. These data suggest that TNF-alpha, IL-8, and mast cells play a fundamental role in PMN recruitment following immune complex injury.