The avermectins are a complex of chemically related agents which exhibit extraordinarily potent anthelmintic activity. They are produced by a novel species of actinomycete, NRRL 8165, which we have named Streptomyces avermitilis . The morphological and cultural characteristics which differentiate the producing organism from other species are described. The avermectins have been identified as a series of macrocyclic lactone derivatives which, in contrast to the macrolide or polyene antibiotics, lack significant antibacterial or antifungal activity. The avermectin complex is fully active against the gastrointestinal nematode Nematospiroides dubius when fed to infected mice for 6 days at 0.0002% of the diet. Fermentation development, including medium modification and strain selection, resulted in increasing the broth yields from 9 to 500 μg/ml.

The nonobese diabetic (NOD) mouse, a model of human type I diabetes, develops insulitis beginning at 4-6 wk of age. By 30 wk of age, 72% of females and 39% of males develop spontaneous diabetes, apparently because of an overwhelming autoimmune response to the insulin-producing beta-cells within the islets. To identify the immune mechanism responsible for destruction of beta-cells in the NOD mouse, we developed an adoptive transfer protocol that induces diabetes in NOD mice at an age when spontaneous diabetes is rarely observed. Splenocytes from overtly diabetic NOD mice were unable to transfer diabetes to very young (less than or equal to 6 wk) irradiated NOD mice but effectively transferred diabetes to irradiated NOD mice greater than 6 wk of age. In such transfers, overt diabetes was induced within 12-22 days in greater than 95% (79/82) of the recipients. Thus, transfer of splenocytes to young mice induces them to become diabetic at a higher frequency and at a younger age than their untreated littermates. Equally successful transfers with as few as 5 X 10(6) spleen cells have been performed in male and female NOD mice, even though males display a lower spontaneous incidence of diabetes than females. Splenocytes obtained from diabetic mice maintained on insulin for up to 2 mo also transferred diabetes. Because NOD mice display increasing levels of insulitis with age, spleen cells obtained from nondiabetic NOD mice of different ages were tested for their ability to transfer diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)

SummaryThe development of autoimmune diabetes in the nonobese diabetic (NOD) mouse is controlled by multiple genes. At least one diabetogenic gene is linked to the major histocompatibility complex (MHC) of the NOD and is most likely represented by the two genes encoding the c~ and chains of the unique NOD class II molecule. Three other diabetogenic loci have recently been identified in the NOD mouse and are located on chromosomes 1, 3, and 11. In addition to the autoimmune diabetes which is caused by destruction of the insulin-producing B cells in the pancreas, other manifestations of autoimmunity are seen in the NOD mouse. These include mononuclear cell inflammation of the submandibular and lacrimal glands, as well as the presence of circulating autoantibodies. To determine the effect of the non-MHC diabetogenic genes on the development of autoimmunity, we constructed the NOD.B10-H-2 b (NOD.H-2 b) strain, which possesses the non-MHC diabetogenic genes from the NOD mouse, but derives its MHC from the C57BL/10 (B10) strain. The NOD.H-2 ~ strain does not develop insulitis, cyclophosphamide-induced diabetes, or spontaneous diabetes. It does, however, develop extensive lymphocytic infiltrates in the pancreas and the submandibular glands that are primarily composed of Thy 1.2 + T cells and B220 + B cells. In addition, autoantibodies are present in NOD.H-2 ~ mice which recognize the "polar antigen" on the insulin-secreting rat tumor line RINm38. These observations demonstrate that the non-MHC genes in the NOD strain, in the absence of the NOD MHC, significantly contribute to the development of autoimmunity. The contribution of a single dose of the NOD MHC to autoimmunity was assessed with a (NOD x NOD.H-2b)F1 cross. Although only '~3% of F1 females developed spontaneous diabetes, approximately 50% of both female and male F1 mice developed insulitis, and 25% of females and 17% of males became diabetic after treatment with cyclophosphamide. These data demonstrate that the MHC-linked diabetogenic genes of the NOD mouse are dominant with decreasing levels of penetrance for the following phenotypes: insulitis > cyclophosphamide-induced diabetes > spontaneous diabetes.T he nonobese diabetic (NOD) 1 mouse spontaneously develops autoimmune diabetes and is an experimental model of human type I diabetes. We previously determined in out-1 Abbreviation used in this paper: NOD, nonobese diabetic. crosses to the C57BL/10 (B10) strain, that at least one gene linked to the MHC of the NOD and three non-MHC-linked recessive diabetogenic genes present in the NOD mouse were required for the development of diabetes (1). Recently, using an outcross with the B10.NOD-H-2g 7 (B10.H-2g 7) strain (a B10 congenic mouse whose MHC was derived from the NOD

Autoimmune, insulin-dependent diabetes mellitus in man is an inherited disease . Many studies have demonstrated (reviewed in references 1, 2) that genes linked to the MHC of man contribute to the genetic susceptibility to diabetes . >90% of Caucasian patients suffering from type 1 diabetes express the DR3 and/or DR4 antigens as compared with a 60% expression in the total population . Interestingly, DR3/DR4 heterozygotes are particularly susceptible to the development of diabetes since up to 50% of type 1 diabetics possess this genotype as compared with only 5% of the general population . The fine specificity of the association of DR3 and DR4 with diabetes has recently been defined using HLA restriction endonuclease fragment length polymorphisms (3-5) and human T lymphocyte clones that define DR subtypes (6, 7).The autoimmune response in type 1 diabetes is characterized by insulitis, which is an inflammatory infiltrate affecting the islets of Langerhans . In a study of 60 recent-onset type 1 diabetics, insulitis was present in 78% of patients (8).A persistence of memory cells specific for insulin-producing a cells is suggested by the observation that long-term insulin-dependent patients receiving a pancreas transplant from an identical twin will still reject the islet tissue even though the original antigenic stimulus has been absent for years (9).Recently, two animal models exhibiting spontaneous diabetes mellitus have been identified . The BB rat (10, 11) and the nonobese diabetic (NOD)' mouse (12-16) both evidence the destructive autoimmune pancreatic insulitis that is characteristic of human type 1 diabetes . In the BB rat model, diabetes can be adoptively transferred with Con A-activated splenic lymphocytes obtained from diabetic BB rats (17,18). Further evidence supporting the autoimmune etiology of diabetes in the BB rat is that treatment of BB rats with a combination of immunosuppressive agents, which included cyclosporine A, glucocorticoids, and

On July 23, 2014, the FDA granted accelerated approval to idelalisib (Zydelig tablets; Gilead Sciences, Inc.) for the treatment of patients with relapsed follicular B-cell non-Hodgkin lymphoma or relapsed small lymphocytic lymphoma (SLL) who have received at least two prior systemic therapies. In a multicenter, single-arm trial, 123 patients with relapsed indolent non-Hodgkin lymphomas received idelalisib, 150 mg orally twice daily. In patients with follicular lymphoma, the overall response rate (ORR) was 54%, and the median duration of response (DOR) was not evaluable; median follow-up was 8.1 months. In patients with SLL, the ORR was 58% and the median DOR was 11.9 months. One-half of patients experienced a serious adverse reaction of pneumonia, pyrexia, sepsis, febrile neutropenia, diarrhea, or pneumonitis. Other common adverse reactions were abdominal pain, nausea, fatigue, cough, dyspnea, and rash. Common treatment-emergent laboratory abnormalities were elevations in alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase, absolute lymphocytes, and triglycerides. Continued approval may be contingent upon verification of clinical benefit in confirmatory trials.