American College of Rheumatology and Food and Drug Administration Summit: Summary of the Meeting, May 17-18, 2022.

The American College of Rheumatology and the US Food and Drug Administration co-sponsored a public meeting in May 2022 about challenges in the clinical development of drugs for rheumatoid arthritis (RA) and psoriatic arthritis (PsA), focusing on innovative clinical trial designs, outcome measures, and data collection methods. Recommendations include early dose-ranging studies and use of active comparators. Challenges and opportunities in assessing long-term safety by leveraging real-world data from electronic health records (EHRs) and claims data are discussed, along with insights from European registries and the evolving role of real-world evidence and artificial intelligence in regulatory evaluations. Endpoints for assessing disease activity and outcome measures used in RA and PsA trials are explored, emphasizing challenges in defining remission, assessing clinical response, and evaluating structural progression. The need for outcome measures that better reflect treatment targets and the potential of advanced imaging in future trials are highlighted. Challenges with placebo-controlled trials in RA are discussed and use of non-inferiority clinical trial design, in which new drugs are evaluated with active comparators, is proposed. Pragmatic trials in RA and PsA, employing decentralized approaches, are highlighted for their real-world relevance and administrative efficiencies. Strategies for identifying at-risk populations for RA and the challenges of using EHRs and insurance claims data in drug development are discussed. Registry data and digital health technologies show promise in bridging the gap between clinical trials and real-world effectiveness.

Clinical pharmacology considerations for the approval of belimumab for the treatment of adult patients with active lupus nephritis: A regulatory perspective.

On 16 December 2020, FDA approved Benlysta® (belimumab) for both the intravenous (IV) and subcutaneous (SC) administration routes for the treatment of adult patients with active lupus nephritis (LN) who are receiving standard therapy. This approval represents the first FDA approved treatment of patients with active LN.The approved IV dosing regimen (10 mg/kg dose Q2W for three doses, then 10 mg/kg Q4W thereafter) was based on a randomized double-blind placebo controlled clinical trial in adult patients with LN. For the approval of the SC dosing regimen (400 mg dose QW for four doses, then 200 mg QW thereafter), efficacy was supported solely by pharmacokinetics (PK) modeling and simulation which estimated a matched steady state average concentration and higher trough concentrations for the SC administration route, for bridging to the efficacy of IV belimumab in adults with LN. The safety and immunogenicity profile of the SC administration route has been assessed in the SLE studies.In a population PK analysis, higher proteinuria was associated with greater belimumab clearance and lower belimumab exposure. In an exposure response analysis, the efficacy of belimumab as evaluated by renal response was mainly driven by patients with lower proteinuria at baseline regardless of other baseline characteristics (e.g. baseline renal function, renal biopsy classification), induction therapies, or belimumab exposure levels (within 10 mg/kg dosing regimen), etc. However, post hoc analyses showed that belimumab had activity in LN patients with higher proteinuria at baseline. There is no adequate information to suggest that a higher dose would provide additional benefit for patients with lower exposure (e.g. higher proteinuria).

Noninferiority Trials to Evaluate Drug Effects in Rheumatoid Arthritis.

OBJECTIVE: The increased availability of highly effective treatments in rheumatoid arthritis (RA) necessitates a reexamination of study designs evaluating new treatments. We undertook this study to discuss possible specifications and considerations of noninferiority (NI) trials assessing drug effects in RA. METHODS: We focused on the use of approved tumor necrosis factor inhibitors (TNFi) as potential active controls and reviewed previous placebo-controlled studies. We summarized the similarities in baseline characteristics and study design of the historical placebo-controlled studies used. After performing meta-analyses to estimate the effects of TNFi on symptoms, physical function, and radiographic progression in RA, we proposed NI margins and evaluated the feasibility of NI trials in this therapeutic setting. RESULTS: We determined that an NI trial comparing an experimental treatment to a TNFi using the symptomatic end point of the American College of Rheumatology 20% improvement criteria response can feasibly provide evidence of a treatment effect, with a 12% absolute difference as one possible appropriate NI margin. For change from baseline in the Health Assessment Questionnaire disability index score, reasonable margins range from 0.10 to 0.12. In evaluating radiographic progression, an appropriate margin and the corresponding feasibility of the trial are dependent on the selected active control and the expected variability in progression. CONCLUSION: Active-controlled studies in RA with justified NI margins can provide persuasive evidence of treatment effects on symptomatic, functional, and radiographic end points. Such studies can also provide reliable, controlled safety data and relevant information for treatment decisions in clinical practice. Thus, we recommend considering NI designs in future clinical trials in RA.

Terpenoids in the Essential Oil and Concentrated Aromatic Products Obtained from Nicotiana glutinosa L. Leaves.

N. glutinosa L. is a relatively less studied Nicotiana species (Solanaceae), although there are data about its importance as a model plant in viral control studies, as a gene donor in tobacco hybridization and as a source of agents with insecticidal or fungicidal effects. The biological activities of the species were associated mostly with the presence of leaf surface metabolites, in particular diterpenes and sucrose esters. The aim of this study was to identify the chemical composition of the essential oil (EO) and two aromatic extraction products (concrete and resinoid) obtained from N. glutinosa L. leaves. GC-MS analysis identified 26 components in the EO (representing 97.3% of total oil content), which contained mostly diterpene compounds with major components manool (14.2%), sclarene (8.4%) and manoyl oxide (8.1%). The number of compounds identified in the concrete was 37 (95.5% of the total content) and the major component was the diterpene alcohol sclareol (14.2%). In the resinoid, 30 volatile components (representing 95.1% of resinoid content) were identified, with major components nicotine (32.9%), α-tocopherol (8.2%), tridecanoin (6.9%), sclareol (6.9%), and solanone (6.9%). The group of bicyclic diterpenes had the largest share in the diterpene fraction of the products (57.3%, 91.7%, and 86.3%, respectively for the EO, concrete, and resinoid). Considering the abundance of sclareol in the aromatic products, the antimicrobial activity of the pure substance was determined. Sclareol was highly effective against a set of medicinally important yeasts; Candida albicans АТСС 10231, C. glabrata ATCC 90030, C. parapsilosis clinical isolate, and C. tropicalis NBIMCC 23, while being less effective against the studied Gram-positive and Gram-negative bacteria. Data from the study on N. glutinosa aromatic products composition may be of interest to the aroma industries for their possible use in perfumery and cosmetics.

An ultrahot gas-giant exoplanet with a stratosphere.

Infrared radiation emitted from a planet contains information about the chemical composition and vertical temperature profile of its atmosphere. If upper layers are cooler than lower layers, molecular gases will produce absorption features in the planetary thermal spectrum. Conversely, if there is a stratosphere-where temperature increases with altitude-these molecular features will be observed in emission. It has been suggested that stratospheres could form in highly irradiated exoplanets, but the extent to which this occurs is unresolved both theoretically and observationally. A previous claim for the presence of a stratosphere remains open to question, owing to the challenges posed by the highly variable host star and the low spectral resolution of the measurements. Here we report a near-infrared thermal spectrum for the ultrahot gas giant WASP-121b, which has an equilibrium temperature of approximately 2,500 kelvin. Water is resolved in emission, providing a detection of an exoplanet stratosphere at 5σ confidence. These observations imply that a substantial fraction of incident stellar radiation is retained at high altitudes in the atmosphere, possibly by absorbing chemical species such as gaseous vanadium oxide and titanium oxide.

Tumor progression locus 2 reduces severe allergic airway inflammation by inhibiting Ccl24 production in dendritic cells.

BACKGROUND: The molecular and cellular pathways driving the pathogenesis of severe asthma are poorly defined. Tumor progression locus 2 (TPL-2) (COT, MAP3K8) kinase activates the MEK1/2-extracellular-signal regulated kinase 1/2 MAP kinase signaling pathway following Toll-like receptor, TNFR1, and IL-1R stimulation. OBJECTIVE: TPL-2 has been widely described as a critical regulator of inflammation, and we sought to investigate the role of TPL-2 in house dust mite (HDM)-mediated allergic airway inflammation. METHODS: A comparative analysis of wild-type and Map3k8-/- mice was conducted. Mixed bone marrow chimeras, conditional knockout mice, and adoptive transfer models were also used. Differential cell counts were performed on the bronchoalveolar lavage fluid, followed by histological analysis of lung sections. Flow cytometry and quantitative PCR was used to measure type 2 cytokines. ELISA was used to assess the production of IgE, type 2 cytokines, and Ccl24. RNA sequencing was used to characterize dendritic cell (DC) transcripts. RESULTS: TPL-2 deficiency led to exacerbated HDM-induced airway allergy, with increased airway and tissue eosinophilia, lung inflammation, and IL-4, IL-5, IL-13, and IgE production. Increased airway allergic responses in Map3k8-/- mice were not due to a cell-intrinsic role for TPL-2 in T cells, B cells, or LysM+ cells but due to a regulatory role for TPL-2 in DCs. TPL-2 inhibited Ccl24 expression in lung DCs, and blockade of Ccl24 prevented the exaggerated airway eosinophilia and lung inflammation in mice given HDM-pulsed Map3k8-/- DCs. CONCLUSIONS: TPL-2 regulates DC-derived Ccl24 production to prevent severe type 2 airway allergy in mice.

Early responses to adenoviral-mediated transfer of the aquaporin-1 cDNA for radiation-induced salivary hypofunction.

No conventional therapy exists for salivary hypofunction in surviving head and neck cancer patients with Radiation Therapy Oncology Group late grade 2-3 toxicity. We conducted a phase I clinical trial to test the safety and biologic efficacy of serotype 5, adenoviral-mediated aquaporin-1 cDNA transfer to a single previously irradiated parotid gland in 11 subjects using an open label, single-dose, dose-escalation design (AdhAQP1 vector; four dose tiers from 4.8 × 10(7) to 5.8 × 10(9) vector particles per gland). Treated subjects were followed at scheduled intervals. Multiple safety parameters were measured and biologic efficacy was evaluated with measurements of parotid salivary flow rate. Symptoms were assessed with a visual analog scale. All subjects tolerated vector delivery and study procedures well over the 42-d study period reported. No deaths, serious adverse events, or dose-limiting toxicities occurred. Generally, few adverse events occurred, and all were considered mild or moderate. No consistent changes were found in any clinical chemistry and hematology parameters measured. Objective responses were seen in six subjects, all at doses <5.8 × 10(9) vector particles per gland. Five of these six subjects also experienced subjective improvement in xerostomia. AdhAQP1 vector delivery to a single parotid gland was safe and transfer of the hAQP1 cDNA increased parotid flow and relieved symptoms in a subset of subjects.

A novel hybrid adenoretroviral vector with more extensive E3 deletion extends transgene expression in submandibular glands.

Salivary glands are an attractive target for gene transfer. Salivary epithelial cells are considered to be highly differentiated and have low rates of cell division (~6 months), affording the opportunity to obtain relatively long-term transgene expression in the absence of genomic integration. Here, we report a novel modified hybrid adenoretroviral vector, which provides stable transgene expression in salivary epithelial cells in vivo for up to 6 months in the absence of genomic integration. This modified hybrid vector, Ad(ΔE1/3)LTR(2)EF1α-hEPO, encodes human erythropoietin (hEPO) and differs from a previously developed hybrid vector, AdLTR(2)EF1α-hEPO, by having more extensive E3 gene deletion. Following direct salivary gland gene transfer by retroductal cannulation, rats transduced with Ad(ΔE1/3)LTR(2)EF1α-hEPO had sustained, elevated serum hEPO levels and hematocrits for 6 months (length of experiment), as compared with ~2 months for animals administered the AdLTR(2)EF1α-hEPO vector. Immunohistochemistry demonstrated that this novel vector could transduce both acinar and ductal cells. Interestingly, the Ad(ΔE1/3)LTR(2)EF1α-hEPO vector evoked much weaker local (salivary gland) immune responses than seen after AdLTR(2)EF1α-hEPO vector delivery, which likely permits its significantly lengthened transgene expression in this tissue.

Systemic autoimmunity and defective Fas ligand secretion in the absence of the Wiskott-Aldrich syndrome protein.

Autoimmunity is a surprisingly common complication of primary immunodeficiencies, yet the molecular mechanisms underlying this clinical observation are not well understood. One widely known example is provided by Wiskott-Aldrich syndrome (WAS), an X-linked primary immunodeficiency disorder caused by mutations in the gene encoding the WAS protein (WASp) with a high incidence of autoimmunity in affected patients. WASp deficiency affects T-cell antigen receptor (TCR) signaling and T-cell cytokine production, but its role in TCR-induced apoptosis, one of the mechanisms of peripheral immunologic tolerance, has not been investigated. We find that WASp-deficient mice produce autoantibodies and develop proliferative glomerulonephritis with immune complex deposition as they age. We also find that CD4(+) T lymphocytes from WASp-deficient mice undergo reduced apoptosis after restimulation through the TCR. While Fas-induced cell death is normal, WASp deficiency affects TCR-induced secretion of Fas ligand (FasL) and other components of secretory granules by CD4(+) T cells. These results describe a novel role of WASp in regulating TCR-induced apoptosis and FasL secretion and suggest that WASp-deficient mice provide a good model for the study of autoimmune manifestations of WAS and the development of more specific therapies for these complications.

Pulse pressure and long-term survival after coronary artery bypass graft surgery.

BACKGROUND: Data from longitudinal studies reveal that widened pulse pressure (PP) is a major predictor of coronary heart disease and mortality, but it is unknown whether PP similarly decreases survival after coronary artery bypass graft (CABG) surgery for coronary heart disease. We therefore assessed long-term survival in patients with increased PP at the time of presentation for CABG surgery. METHODS: In this retrospective observational study of patients undergoing CABG surgery between January 1993 and July 2004, 973 subjects were included for assessment of long-term survival. Baseline arterial blood pressure (BP) measurements were defined as the median of the first 3 measurements recorded by the automated record keeping system before induction of anesthesia. The effect of baseline PP on survival after surgery was evaluated using a Cox proportional hazards regression model and bootstrap resampling with baseline mean arterial BP, systolic BP, diastolic BP, diabetes, Hannan risk index, aprotinin use, and cardiopulmonary bypass time as covariates. RESULTS: There were 220 deaths (22.9%) during the follow-up period (median, 7.3 yr [Q1: 5, Q3: 10 yr]) including 94 deaths from cardiovascular causes. Increased baseline PP was a significant predictor of reduced long-term survival (P < 0.001) along with Hannan risk index (P < 0.001), duration of cardiopulmonary bypass (P < 0.001), and diabetes (P < 0.001). Baseline systolic (P = 0.40), diastolic (P = 0.38), and mean arterial BPs (P = 0.78) were not associated with long-term survival. The hazard ratio for PP (adjusted for other covariates in the model) was 1.11 (1.05-1.18) per 10-mm Hg increase. CONCLUSIONS: An increase in perioperative PP is associated with poor long-term survival after CABG surgery. Together with our previous report linking PP to in-hospital fatal and nonfatal vascular complications, the established models for surgical risk assessment, patient counseling, and treatment should be revised to include PP.

Development of a gene transfer-based treatment for radiation-induced salivary hypofunction.

A significant long-term side effect of radiation therapy for head and neck cancers is xerostomia, a dry mouth, due to salivary gland damage. Despite continuing efforts to eliminate this problem, many patients continue to suffer. This brief review describes our efforts to develop a gene transfer approach, employing the aquaporin-1 cDNA, to treat patients with existing radiation-induced salivary hypofunction. A Phase I/II clinical trial, using a recombinant adenoviral vector to mediate gene transfer, is currently underway.

Transient detection of E1-containing adenovirus in saliva after the delivery of a first-generation adenoviral vector to human parotid gland.

BACKGROUND: Radiation-induced salivary hypofunction is a common side-effect of treatment for head and neck cancers. Patients suffer significant morbidity and there is no suitable conventional therapy. We are conducting a Phase I clinical trial, using a first-generation serotype 5 adenoviral (Ad5) vector encoding human aquaporin-1 (AdhAQP1) to treat such patients. One week after the administration of AdhAQP1 to an enrolled, generally healthy patient, E1-containing adenovirus was detected in parotid saliva. METHODS: The real-time quantitative polymerase chain reaction (PCR) was used to measure the Ad5 E1 gene and AdhAQP1 in saliva and serum. PCR and sequencing were used to characterize viral/vector DNA extracted from saliva. The presence of infectious adenovirus was assessed by the inoculation of A549 cells with aliquots of saliva. Serum Ad5 neutralizing antibodies were measured by the inhibition of 293-cell transduction with an Ad5 vector encoding luciferase. Multiple clinical evaluations were performed. RESULTS: On day 7 after AdhAQP1 delivery, low levels of the Ad5 E1 gene were detected in parotid saliva (82 copies/microl). In addition, significant levels of AdhAQP1 were also detected (1.5 x 10(3) copies/microl). The patient was asymptomatic and subsequent analysis of parotid saliva samples prior to day 7 and after day 7 until day 42 was negative for both virus and vector. No virus or vector was detected in serum at any time. Detailed PCR analyses of DNA extracted from the day 7 parotid saliva sample suggested the absence of a recombination event, and no infectious virus was found. CONCLUSIONS: The patient most likely had a latent Ad5 infection in the targeted parotid gland that was activated after gene transfer and was without clinical consequence.

Pathogenesis of Sjögren's syndrome.

PURPOSE OF REVIEW: To summarize recent developments in our understanding of the pathogenesis of Sjögren's syndrome with a focus on the relationship between inflammation and exocrine dysfunction. RECENT FINDINGS: Animal models demonstrated the complex interactions between immunologic and nonimmunologic mechanisms in Sjögren's syndrome. Activation of the innate immune system can lead to exocrine dysfunction before or without significant inflammation, whereas in other models, salivary gland function is preserved despite intense inflammatory infiltrates. Primary or inflammation-related abnormalities in water channels contribute to the exocrinopathy. Activation of the innate immunity in patients is demonstrated by the upregulation of type-1 interferon-regulated genes (interferon signature) in peripheral blood and salivary glands and abnormal expression of B cell-activating factor and its receptors. Nonimmune mechanisms that may contribute to exocrine dysfunction include local and systemic androgen deficiency and autonomic nervous system dysfunction. Autoantibodies against the muscarinic acetylcholine receptors would provide a link between autoimmunity and exocrine dysfunction, but the data on the presence, frequency and physiologic affect of these antibodies remain controversial. SUMMARY: Recent discoveries from studies in patients with Sjögren's syndrome and animal models suggest a complex interplay between genetic factors, environmental and stochastic events that involve innate and adaptive immunity, hormonal mechanisms and the autonomic nervous system. Some of these findings suggest that exocrine gland dysfunction may precede autoimmunity or represent a process independent from inflammation in the pathogenesis of Sjögren's syndrome.

Aquaporin-1 gene transfer to correct radiation-induced salivary hypofunction.

Irradiation damage to salivary glands is a common iatrogenic consequence of treatment for head and neck cancers. The subsequent lack of saliva production leads to many functional and quality-of-life problems for affected patients and there is no effective conventional therapy. To address this problem, we developed an in vivo gene therapy strategy involving viral vector-mediated transfer of the aquaporin-1 cDNA to irradiation-damaged glands and successfully tested it in two pre-clinical models (irradiated rats and miniature pigs), as well as demonstrated its safety in a large toxicology and biodistribution study. Thereafter, a clinical research protocol was developed that has received approval from all required authorities in the United States. Patients are currently being enrolled in this study.

Technology Insight: hematopoietic stem cell transplantation for systemic rheumatic disease.

Hematopoietic stem cells (HSCs) have the capacity for self-renewal and the potential to differentiate into all types of hematopoietic and immune system cells. These features have been successfully used to treat a multitude of hematologic malignancies and nonmalignant diseases such as aplastic anemia, hemoglobinopathies, inborn errors of metabolism and congenital immunodeficiency states. The application of HSC transplantation has been expanded over the past decade to include immune-mediated diseases such as multiple sclerosis, treatment-refractory rheumatoid arthritis, systemic lupus erythematosus and systemic sclerosis. Transplantation of HSCs for the treatment of autoimmune diseases aims to fundamentally correct the dysregulated immune system, which could result in sustained clinical remission or potential cure. The use of this approach is currently restricted to clinical research, as there is no standard conditioning regimen to attain these aims in autoimmune diseases. HSC transplantation is associated with inherent morbidity and mortality, both treatment-related and disease-related, and selecting the correct group of patients with the best risk:benefit ratio is a challenging task.

Autoimmunity versus tolerance: can dying cells tip the balance?

Apoptosis is a physiological process of self-destruction for cells that are damaged or programmed to die. Apoptosis occurs through a series of regulated events that allow cellular debris to be contained and efficiently phagocytosed without initiating a proinflammatory immune response. Recent data have linked physiological apoptosis and the uptake of apoptotic cells by macrophages and some subsets of dendritic cells to the maintenance of peripheral immune tolerance. However, when cells die through necrosis, spilling their intracellular contents, or are infected with various pathogens, activation of antigen-presenting cells and induction of an immune response can occur. Receptors for extrinsic pathogen-associated structures, such as membrane bound Toll-like receptors (TLRs) or intracellular Nod-like receptors (NLRs) can also respond to cross-reactive host molecules from dying cells and may focus autoimmune responses onto these antigens. Several autoimmune disorders have been linked to defects in the apoptotic process. Defective apoptosis of immune cells leads to autoimmunity, as in autoimmune lymphoproliferative syndrome (ALPS) associated with mutations in the death receptor Fas. Defective clearance of apoptotic cell debris can also lead to autoantibody production. We will discuss how cell death and apoptotic cell clearance may affect the finely tuned balance between peripheral immune tolerance and autoimmunity.

Diagnosis and treatment of vasculitis of the central nervous system in a patient with systemic lupus erythematosus.

BACKGROUND: A 23-year-old white woman with a 3-year history of systemic lupus erythematosus and a 15-month history of lupus nephritis and retinal vasculitis was successfully treated with antibiotics for Pseudomonas aeruginosa pneumonia while on moderate doses of corticosteroids. Even though her pneumonia had improved, she developed acute changes in her mental status that rapidly progressed to encephalopathy with coma. INVESTIGATIONS: Physical examination, fundoscopic examination, laboratory tests for metabolic abnormalities, cerebrospinal fluid analysis, microbiology and serologic testing, electroencephalogram, tests for IgM and IgG anticardiolipin antibodies, neuroimaging including CT of the brain and T1-weighted MRI before and after gadolinium contrast, and flow-attenuated inversion recovery MRI. DIAGNOSIS: Vasculitis of the central nervous system associated with systemic lupus erythematosus. MANAGEMENT: Intravenous methylprednisolone 1,000 mg/day for 3 days, one dose of intravenous pulse cyclophosphamide 750 mg/m(2), intravenous immunoglobulin 400 mg/kg/day for 4 days, plasmapheresis on alternate days for five cycles, and prednisone 40 mg/day. She continued monthly doses of intravenous pulse cyclophosphamide and intravenous pulse methylprednisolone for 6 months, followed by maintenance infusions every 3 months over 2 years. Prednisone was tapered over 18 months. Cyclophosphamide was discontinued after 2 years because of poor bone-marrow tolerance, and was replaced with mycophenolate mofetil 3,000 mg/ day and ciclosporin 50 mg twice daily.

Granulocytic invasion of the central nervous system after hematopoietic stem cell transplantation for systemic lupus erythematosus.

We report on the likely mechanism of an exacerbation of neurological symptoms developed during immune reconstitution after autologous non-myeloablative hematopoietic stem cell transplantation in a 33-year-old man with systemic lupus erythematosus- associated recurrent transverse myelitis. Cerebrospinal fluid examination revealed prominent neutrophilic pleocytosis and no evidence of infection or of reactivation of lupus. Following a course of corticosteroid treatment the exacerbation resolved completely and the patient's neurological function continued to improve, resulting in net gain above pre-treatment for over 1 year follow-up without maintenance immunosuppression. Granulocytic invasion of the central nervous system represents a novel and possibly preventable cause of neurological complications during haematologic reconstitution.

Progressive glomerulonephritis and histiocytic sarcoma associated with macrophage functional defects in CYP1B1-deficient mice.

The cytochrome P450 CYP1B1 enzyme metabolically activates polycyclic aromatic hydrocarbons and is a major P450 isoenzyme in human monocytes and macrophages. We have shown previously that mice deficient in CYP1B1 were resistant to induced tumors after 7,12-dimethylbenz[a]anthracene exposure. The pathology of aging CYP1B1 null mice on a B6; 129 background was studied in groups of 29 males and 30 females. By 12 months, 50% of the female mice had developed a unusual progressive glomerulonephritis while males had similar renal lesions later in life. This disease followed a sequence of proliferative, membranoproliferative and sclerotic glomerulonephritis. Anti-DNA antibodies were found in the blood of the mice along with immune deposits containing immunoglobulins in subepithelial locations of the glomerular basement membrane. The lesions were unlike those found in aging wild-type B6;129 mice or mice of other strains. We found that macrophages from CYP1B1-null mice were impaired in the phagocytosis of apoptotic, necrotic, and opsonized cells. This suggests a generalized defect in the phagocytic activity of CYP1B1-null mouse macrophages. Male mice also developed a high incidence (62-64%) of histiocytic sarcomas. Our study provides evidence that deficiency of CYP1B1 can play a role in the development of glomerular disease, normal processing of catabolic DNA and tumors of the mononuclear phagocyte system. The function of CYP1B1 in histiocytes and macrophages may involve both self-tolerance and tumor suppression.