Impact of bone marrow-derived mesenchymal stromal cells on experimental xenogeneic graft-versus-host disease

Abstract

Background aims. Graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation caused by donor T cells reacting against host tissues. Previous studies have suggested that mesenchymal stromal cells (MSCs) could exert potent immunosuppressive effects. Methods. The ability of human bone marrow derived MSCs to prevent xenogeneic GVHD in non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice and in NOD/SCID/interleukin-2Rg(null) (NSG) mice transplanted with human peripheral blood mononuclear cells (PBMCs) was assessed. Results. Injection of 200 Â 10 6 human PBMCs intraperitoneally (IP) into sub-lethally (3.0 Gy) irradiated NOD/SCID mice also given anti-asialo GM 1 antibodies IP 1 day prior and 8 days after transplantation induced lethal xenogeneic GVHD in all tested mice. Co-injection of 2 Â 10 6 MSCs IP on day 0 did not prevent lethal xenogeneic GVHD induced by injection of human PBMCs. Similarly, injection of 30 Â 10 6 human PBMCs IP into sub-lethally (2.5 Gy) irradiated NSG mice induced a lethal xenogeneic GVHD in all tested mice. Injection of 3 Â 10 6 MSCs IP on days 0, 7, 14 and 21 did not prevent lethal xenogeneic GVHD induced by injection of human PBMCs. Conclusions. Injection of MSCs did not prevent xenogeneic GVHD in these two humanized mice models.

Mechanisms of Immune Suppression Utilized by Canine Adipose and Bone Marrow-Derived Mesenchymal Stem Cells

“…For example, MSC derived from adipose tissues or bone marrow have been used to treat experimental allergic encephalitis, inflammatory bowel disease, immune-mediated arthritis, airway inflammation, and graft-versus-host disease in rodent models [1,[9][10][11][12]. In addition, human MSC have been administered to rodent models of inflammatory diseases [13][14][15][16][17]. Thus, it is apparent that the immune modulatory properties of MSC can be utilized therapeutically in a number of different diseases settings.…”

Thinking Out of the Box—New Approaches to Controlling GVHD

“…Taken together, these studies suggested that a single injection of (non-activated) MSC given on day 0 failed to prevent GVHD in most models [71,73,77,78], while a single infusion of activated MSC on day 0 [73], or repeated MSC injections at the time of and after transplantation showed clinical benefit in some [72,76,77] but not all [74,75,78] studies, depending on the GVHD model, the timing of MSC infusion, the dose of MSC infused, as well as the origin of MSC. However, repeated MSC injection failed to prevent lethal GVHD in a pre-clinical canine model of dog leukocyte antigen-haploidentical transplantation [79].…”

“…A number of studies have assessed the ability of MSC infusion at preventing GVHD in various murine models of GVHD [71][72][73][74][75][76], in humanized murine models of xenogeneic GVHD [77,78], as well as in a preclinical canine model of GVHD [79]. Taken together, these studies suggested that a single injection of (non-activated) MSC given on day 0 failed to prevent GVHD in most models [71,73,77,78], while a single infusion of activated MSC on day 0 [73], or repeated MSC injections at the time of and after transplantation showed clinical benefit in some [72,76,77] but not all [74,75,78] studies, depending on the GVHD model, the timing of MSC infusion, the dose of MSC infused, as well as the origin of MSC.…”

Novel approaches for preventing acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

“…[42] Results were variable, with some studies having reported benefits [131] while others having not. [132] Various factors, including cell dose, timing of infusion, and pre-activated status of MSCs might have added heterogeneity between studies and influenced results. Pilot clinical studies have also suggested a potential role for MSCs as GVHD prevention.…”