Macrophages. By screening Macrophages, Jounce has discovered certain Targets, listed on Exhibit F, that may be useful in treating diseases in the Field (such Targets listed on Exhibit F as of the Effective Date under the column “Available Macrophage Targets” the “Initial Macrophage Targets”). During the Research Term, as part of the Collaboration, Jounce may (a) perform various screens in accordance with Section 2.2.2(a) to identify, or (b) otherwise Develop alone or with Third Parties, for each of (a) and (b), additional potential Targets (other than Excluded Jounce Targets and Excluded Celgene Targets) expressed by Macrophages which, by binding of a Biologic (Developed by or on behalf of Jounce) to an applicable Target on such Macrophage or by binding of a Biologic (Developed by or on behalf of Jounce) that is a ligand trap that contains such Target or a fragment thereof, causes significant Immune Activation or Immune Suppression (together with the Initial Macrophage Targets, such Targets the “Available Macrophage Targets”)
Macrophages. Type 2 diabetes mellitus . Weight gain Abbreviations CLS Crown-like structure MCP-1 Monocyte chemoattractant protein-1 MMP Matrix metalloproteinase PAI-1 Plasminogen activator inhibitor-1 qPCR Quantitative PCR Introduction Insulin therapy is frequently needed to achieve adequate glycaemic control in patients with type 2 diabetes mellitus yet often results in undesirable weight gain. Although values differ and studies are generally of limited duration, the esti- mated weight gain during the first year of insulin therapy ranges from approximately 2 to 6 kg [1]. This weight gain is paralleled by an increase in abdominal fat mass [1]. When obesity develops, the adipose tissue undergoes dis- tinct morphological changes including adipocyte enlargement and macrophage influx [2]. In adipose tissue in obese individ- uals, macrophages may be arranged in so-called crown-like structures (CLSs) that surround dysfunctional or dying adipo- cytes [3] and are characterised as having a more pro- inflammatory nature than individual macrophages dispersed throughout the adipose tissue [4]. In general, these changes lead to a more pronounced in- flammatory status of the adipose tissue that is reflected by an increased secretion of pro-inflammatory mediators by the adipose tissue and a reduction in secretion of the insulin- sensitising protein adiponectin [5]. The enhanced inflamma- tory status of the adipose tissue is thought to contribute to the development of systemic insulin resistance that may eventu- ally evolve into type 2 diabetes. Although inflammatory changes in the adipose tissue are well described in individuals who develop obesity, it remains unknown whether similar changes in the morphological and inflammatory characteris- tics of subcutaneous adipose tissue also occur in patients with type 2 diabetes who start insulin therapy and subsequently gain weight. An emerging body of evidence suggests that insulin sup- presses the inflammatory process, not only through preventing hyperglycemia, but also by modulating key inflammatory molecules. Studies that have examined the effects of (intensive) insulin therapy on immune function and inflam- matory factors have shown that the levels of systemic pro- inflammatory cytokines decrease after administration of insu- lin [6, 7]. One may hypothesise that the anti-inflammatory effects of insulin at the systemic level may be counteracted by the pro- inflammatory changes associated with an increased fat mass. This may be particular...
Macrophages. Microbiota seems to have a variable influence in intestinal macrophage frequency and function. In the absence of bacteria, macrophage numbers in the intestine are either similar or reduced (86, 87). Qualitatively, macrophage activation status and antiviral functionality is reduced in GF conditions or with antibiotic treatment as the expression of activation markers is lessened (88, 89).
Macrophages. The origin of the macrophages is in the bone marrow where myeloid progenitors differentiate into promonocytes and then into circulating monocytes which migrate transendothelially into the various organs to become macrophages. These macrophages are very effective in presenting antigenic peptides to T cells. They occur in almost all organs of the body. Upon fertilization, macrophages flux into the decidualized endometrium, and are found in close association with trophoblasts populations which secrete chemotactic molecules [51]. Macrophages comprise at least 10% of total decidual leukocytes [52]. In the decidua parietalis the trophoblast cells are scarce and also the macrophages are found in few numbers [50]. Macrophages are pluripotent, especially near the end of pregnancy, therefore it is hypothesized that their relative number increase at the end of gestation [52]. The close association of macrophages and extravillous trophoblast cells suggest an early recognition of fetal tissue by the immune system and a role in placental development, possibly by connection with HLA-G. Two types of macrophages populate the decidua, pro-inflammatory CD163- type 1 macrophages and immune modulatory CD163+ type 2 macrophages. Type 1 macrophages produce high levels of IL-12 and have a T cell stimulating potential. Type 2 macrophages do not have the T cell stimulating potential, do have a phagocytosis potential, and produce high levels of IL-10. Several studies show that decidual macrophages may have an immunoinhibitory function at the fetal-maternal interface since these macrophages are not able to differentiate into dendritic cells. Furthermore, they produce IL-10 and IDO and express low levels of the T lymphocyte co-stimulatory molecules CD80 and CD86 [9]. IL-10 can, by blocking the expression of co-stimulatory molecules on APCs, reduce the T cell activity against the fetus [53]. 1 Granulocytes T cells Mast cells Macrophages B cells NK cells Gestational age Relative leukocyte density Figure 6 Leukocytes in human decidua. The relative leukocyte density at the fetal-maternal interface and the relation with gestational age is shown. Adjusted from [52]. Dendritic cells Dendritic cells are closely related to macrophages. Dendritic cells have the power to induce primary immune responses and occur in mucosal sites such as skin, airways, gut and decidua. These cells transform information to the adaptive immune system. They also play a role in the induction of immunological toleranc...
