Rabbit Polyclonal Mouse Antithymocyte Globulin Administration Alters Dendritic Cell Profile and Function in NOD Mice to Suppress Diabetogenic Responses

Abstract

Mouse antithymocyte globulin (mATG) prevents, as well as reverses, type 1 diabetes in NOD mice, through mechanisms involving modulation of the immunoregulatory activities of T lymphocytes. Dendritic cells (DC) play a pivotal role in the generation of T cell responses, including those relevant to the autoreactive T cells enabling type 1 diabetes. As Abs against DC are likely generated during production of mATG, we examined the impact of this preparation on the phenotype and function of DC to elucidate novel mechanisms underlying its beneficial activities. In vivo, mATG treatment transiently induced the trafficking of mature CD8− predominant DC into the pancreatic lymph node of NOD mice. Splenic DC from mATG-treated mice also exhibited a more mature phenotype characterized by reduced CD8 expression and increased IL-10 production. The resultant DC possessed a potent capacity to induce Th2 responses when cultured ex vivo with diabetogenic CD4+ T cells obtained from BDC2.5 TCR transgenic mice. Cotransfer of these Th2-deviated CD4+ T cells with splenic cells from newly diabetic NOD mice into NOD.RAG−/− mice significantly delayed the onset of diabetes. These studies suggest the alteration of DC profile and function by mATG may skew the Th1/Th2 balance in vivo and through such actions, represent an additional novel mechanism by which this agent provides its beneficial activities.

Immune reconstitution after anti-thymocyte globulin-conditioned hematopoietic cell transplantation

“…This observation is consistent with the known negative impact of GVHD and/or its treatment on B-lymphopoiesis (44–47). There also appears to be a GVHD-independent effect of ATG (Supplementary Figure 3) which we hypothesize is related to the known positive effect of ATG on Th2 cells (48). For memory/effector CD8 T cells, the reason is not clear.…”

Anti-thymocyte globulin (ATG) differentially depletes naïve and memory T cells and permits memory-type regulatory T cells in nonobese diabetic mice

“…It may also influence the interaction between T cells and endothelial cells through modulating expression of adhesion molecules [22]. Our recent study showed that ATG therapy eliminated certain subset of dendritric cells and induced tolerogenic dendritic cells [10]. In addition, ATG therapy may facilitate tolerance induction through ATG-mediated apoptosis of T cells; because T cell apoptosis induced by anti-CD3 therapy was recently demonstrated to be associated with CD3 antibody therapy-induced immune tolerance [23].…”

“…However, recent data suggests that ATG therapy induces immune modulation beyond that of simple T cell depletion [9]. For example, ATG therapy may facilitate tolerance induction through modulation of dendritic cells (DC), both phenotypically and functionally [10]. Evidence has also shown that ATG therapy may also induce regulatory T cells (Tregs) in vivo [11-13].…”

Kidney-Derived Mesenchymal Stromal Cells Modulate Dendritic Cell Function to Suppress Alloimmune Responses and Delay Allograft Rejection

“…Spleen and draining LN (left renal LN) were harvested to analyze CD4 ϩ CD25 ϩ FOXP3 ϩ regulatory T-cell populations by intracellular staining and flow cytometry. Splenocytes were analyzed for tumor necrosis factor-␣-and interferon-␥-producing T cells by intracellular staining and flow cytometry, as previously described (12).…”