Splenic Macrophages From the NOD Mouse Are Defective in the Ability to Present Antigen

Abstract

IDDM results from the destruction of pancreatic beta-cells by autoreactive T-cells that appear to avoid deletion early in development, possibly due to improper interaction with antigen-presenting cells (APCs) resident in the thymus or periphery. In the nonobese diabetic (NOD) mouse, there exists a defect in APC function characterized by its failure to fully mature upon stimulation. The NOD mouse thus provides an excellent model for the investigation of APC dysfunction and development and how these relate to the incidence of autoimmune diabetes. We initiated studies of APC function in the NOD mouse with respect to antigen processing and presentation, using a well-characterized antigen hen egg lysozyme (HEL) and comparing it with the closely related, major histocompatibility complex (MHC) (I-Ag7) identical, diabetes-resistant mouse strain NOR. Proliferation assays comparing NOD and NOR HEL-specific T-cells demonstrated that the T-cell proliferation response of the NOD mouse to both native and denatured forms of the antigen is lower than that of NOR. When crisscross proliferation experiments were conducted using purified T-cells and irradiated spleen cells as APCs from both strains, the results demonstrated that the defect in proliferation resided in the APC compartment of activation. The levels of intracellular glutathione (GSH) were compared in splenic macrophages from NOD and NOR mice; it was found that on antigenic stimulation, NOR macrophages produced significantly more intracellular GSH than did NOD macrophages, even under hyperglycemic (50 mmol/l glucose) conditions. The lower amount of GSH seen in the NOD may result in less efficient processing of antigen, and subsequently, lower levels of T-cell activation.

N‐terminal flanking residues of a diabetes‐associated GAD65 determinant are necessary for activation of antigen‐specific T cells in diabetes‐resistant mice

“…Multiple immune-related genes involving different biological functions, from antigen processing and presentation to T cell activation, migration and apoptosis, have been suggested as candidates for these Idd loci [17]. Nevertheless, several studies reported abnormal APC function in NOD mice, which might be related to the known T cell dysfunction in this strain [18][19][20].…”

“…Multiple immune-related genes involving different biological functions, from antigen processing and presentation to T cell activation, migration and apoptosis, have been suggested as candidates for these Idd loci [17]. Nevertheless, several studies reported abnormal APC function in NOD mice, which might be related to the known T cell dysfunction in this strain [18][19][20].We previously identified a region within GAD65, p524-543 (p543), to which spontaneous T cell responses arise in young NOD mice as early as 3-4 weeks of life [1]. Interestingly, this 20mer peptide appeared to be comprised of two distinct determinants: an N-terminal moiety (p524-538 (p524)) and a C-terminal moiety (p530-543 (p530)).…”

Role of M2b Macrophages in the Acceleration of Bacterial Translocation and Subsequent Sepsis in Mice Exposed to Whole Body [137Cs] Gamma-Irradiation

“…NOD/scid IL-2Rg null mice have been defined as immunodeficient mice lacking functional T cells, B cells, and NK cells. Also, these mice have reduced dendritic functions and defective Mf (14)(15)(16)(17). These mice were treated i.p.…”

DNA vaccination with an insulin construct and a chimeric protein binding to both CTLA4 and CD40 ameliorates type 1 diabetes in NOD mice

“…12 Also, a developmental defect in splenic macrophages of NOD mouse was found responsible for their inability to process and/or present autoantigens in a tolerogenic fashion, while allowing them to retain the capacity to activate autoreactive T cells in the periphery. 13 These defects in costimulatory molecules might result in insufficient presenting of antigen signals contributing to deficiently activated (suboptimal) T cells unable to undergo negative selection but sufficient to mount autoimmunity. [14][15][16][17] It has been indicated that in NOD mice, the islet-reactive T cells were refractory to CTLA-4 and their ability to escape peripheral regulation might be greatly increased as well.…”