Combination Treatment with Antigen-Specific Dual-Sized Microparticle System Plus Anti-CD3 Immunotherapy Fails to Synergize to Improve Late-Stage Type 1 Diabetes Prevention in Nonobese Diabetic Mice.

Type 1 diabetes (T1D) pathophysiology, while incompletely understood, has in part been attributed to aberrant presentation of self-antigen plus proinflammatory costimulation by professional antigen-presenting cells (APCs). Therapies targeting dendritic cells (DCs) offer an avenue to restore antigen-specific tolerance by promoting presentation of self-antigen in an anti-inflammatory or suppressive context. Here, we describe a subcutaneously administered, dual-sized biodegradable microparticle (MP) platform that includes phagocytosable (∼1 µm) and nonphagocytosable (∼30 µm) MPs to deliver pro-tolerogenic factors both intra- and extracellularly, as well as the T1D-associated autoantigen, insulin, to DCs for amelioration of autoimmunity. This MP platform resulted in increased recruitment of DCs, suppressive skewing of DC phenotype with diminished expression of CD86 and MHC-II, increased regulatory T cell (Treg) frequency, and upregulated expression of the checkpoint inhibitor programmed cell death protein 1 (PD-1) on T cells. When administered concomitantly with anti-CD3 antibody, which provides transient T cell depletion while preserving Treg populations, in 12-week-old nonobese diabetic (NOD) mice, regulatory immune populations persisted out to 20 weeks of age; however, combination anti-CD3 and dual-sized MP (dMP) therapy failed to synergistically inhibit diabetes onset.

Mobilization without immune depletion fails to restore immunological tolerance or preserve beta cell function in recent onset type 1 diabetes.

Granulocyte colony-stimulating factor (G-CSF) has been used to restore immune competence following chemoablative cancer therapy and to promote immunological tolerance in certain settings of autoimmunity. Therefore, we tested the potential of G-CSF to impact type 1 diabetes (T1D) progression in patients with recent-onset disease [n = 14; n = 7 (placebo)] and assessed safety, efficacy and mechanistic effects on the immune system. We hypothesized that pegylated G-CSF (6 mg administered subcutaneously every 2 weeks for 12 weeks) would promote regulatory T cell (Treg) mobilization to a degree capable of restoring immunological tolerance, thus preventing further decline in C-peptide production. Although treatment was well tolerated, G-CSF monotherapy did not affect C-peptide production, glycated haemoglobin (HbA1c) or insulin dose. Mechanistically, G-CSF treatment increased circulating neutrophils during the 12-week course of therapy (P < 0·01) but did not alter Treg frequencies. No effects were observed for CD4(+) : CD8(+) T cell ratio or the ratio of naive : memory (CD45RA(+)/CD45RO(+)) CD4(+) T cells. As expected, manageable bone pain was common in subjects receiving G-CSF, but notably, no severe adverse events such as splenomegaly occurred. This study supports the continued exploration of G-CSF and other mobilizing agents in subjects with T1D, but only when combined with immunodepleting agents where synergistic mechanisms of action have previously demonstrated efficacy towards the preservation of C-peptide.

Blood lymphocyte chimerism associated with IVF and monochorionic dizygous twinning: case report.

We report on dizygotic (DZ) twins, conceived by IVF and ICSI with assisted hatching, who each had a mixture of 46,XX and 46,XY cells in blood lymphocytes. The female twin had mild genitalia abnormalities but further study revealed anatomically normal reproductive anatomy. Chromosome and fluorescence in situ hybridization studies of buccal, skin and ovarian tissue were normal, as were buccal tissue DNA studies. Fetal ultrasound and fetal membrane pathology were consistent with a monochorionic, diamniotic placenta (MCDAP). These twins thus have blood chimerism but are not chimeric in the other tissues studied. The mechanism for the chimerism could be due to either placental vascular anastamoses (after the development of the haematoblast stem cells) or due to an admixture of trophoblast cells during early blastocyst development. Such trophoblast cell admixtures would be restricted to the extraembryonic tissues so that general physical development in the fetus is normal and without somatic cell chimerism. This case in combination with others previously reported suggests that in IVF conceptions, the prevalence of blood chimerism associated with twinning, and the occurrence of DZ twinning associated with MCDAP, may be higher than previously thought.

Need for primary care.

OBJECTIVE: This paper is a renewed call for medical schools to address the societal need for more primary care physicians. DATA SOURCES: Numerous studies from the literature are cited as background for this paper. DATA SYNTHESIS: The Author retraces the historical beginnings of the specialty of Family Practice and some of the more recent events which highlight the need for more primary care physicians. CONCLUSIONS: The author concludes that there is a societal need for more primary care physicians and that medical schools should respond to this need.

A case report in a Rural Health Center.

An experiment utilizing nurse practitioners in the delivery of health care in a rural Nebraska community is described. In spite of several reorganizations, over a 2 1/2-year period of study, the project failed in terms of patient utilization. Visit rates began at 300 per month and increased to a high of 825 until the community perceived that the nurse practitioner was interposed between themselves and the primary physician. Rates then dropped to 375 and the community withdrew from the project. Implications for rural health projects using ancillary personnel are discussed.