Tolerance-like mediated suppression by mesenchymal stem cells in dust mite allergic asthma.
J Allergy Clin Immunol. 2012 Apr;129(4):1094-101.
Kapoor S, Patel SA, Kartan S, Axelrod D, Capitle E, Rameshwar P.
Department of Medicine, New Jersey Medical School, Rutgers School of Biomedical Health Sciences, Newark, NJ, USA.
Background: Mesenchymal Stem Cells (MSCs) can suppress and enhance immune functions. MSCs show promise as `off the shelf’ cellular therapy for several disorders, including inflammation.
Objective: We investigated the effects of MSCs on the proliferation of peripheral blood mononuclear (PBMCs) to allergic (dust mite, DM) and/or allergic asthma (AA) subjects.
Methods: Proliferation was studied by tritiated thymidine uptake, with or without MSCs. The refractoriness of PBMCs to DM were examined after preconditioned with MSCs and by repeated challenge with low-dose DM. Flow cytometry studied regulatory T-cells (Treg) and dendritic cell (DC). ELISA studied cytokine production.
Results: Seven allergic asthma subjects met the inclusion/exclusion criteria. MSCs significantly (p<0.05) reduced the proliferation of six subjects with allergic asthma, but not allergy alone. The effect was specific to the allergen since MSCs did not affect challenges to Tetanus toxoid. There was no change in CD4/CD25/FoxP3+ cells, although there was decreased IFNγ and increased IL-10. Mature DCs were increased by 6 folds. Refractoriness to DM was achieved by repeated exposure to low dose DM and MSCs and, PBMCs, preconditioned with MSCs.
Conclusion: MSCs suppressed the proliferation of DM-challenged PBMCs from allergic asthma subjects but not from allergic subjects without asthma. MSCs blunted the maturation of DC but not Tregs. Repeated exposure to low dose DM and MSCs as well as preconditioning of PBMCs with MSCs caused refractoriness to DM. These findings have implications for the use of MSCs to attenuate the inflammatory responses to allergic triggers in asthma patients with `off the shelf’.
Mesenchymal stem cells (MSCs) can be obtained from several sources. There is ease in obtaining tissues from the adult bone marrow and adipose for research and clinical application. In other cases, investigators have isolated MSCs from discarded tissues such as the placenta, referred as placenta stem cells. There is overwhelming research on MSCs for all aspects of medicine such as tissue repair. MSCs seem to have an unusual property for transplantation to an unrelated donor, often referred as `off-the-shelf’ cells. This property is highly significant for clinical application because the MSCs will be `on demand’ for clinical application.
Parallel to the research that was conducted with MSCs for tissue repair these stem cells were also studied for their roles as anti-inflammatory cells. The research shows that MSCs can be licensed by an inflammatory milieu to become immune suppressor cells. This property of MSCs in combination with the following points make MSCs attractive for stem cell therapy: ease in obtaining tissues from adults to expand MSCs, reduced ethical concerns with the use of MSCs, ease to expand MSCs to achieve large amounts, ability of MSCs to be transplanted across allogeneic barrier, no evidence of transformation in vivo.
Despite the extensive supporting information on MSCs as anti-inflammatory cells, such therapy has not reached the clinic for allergic inflammation. This led us to ask two questions: Question 1 asked if MSCs can suppress allergen-induced inflammation in immune cells from asthma patients. Question 2 asked if immune tolerance can be achieved when the immune cells are repeatedly exposed to small amounts of the antigen and MSCs. The significance of the second question is to be able to induce long-term anergic response in asthmatic patients.
We selected dust mite (DM) (Der p I) as the choice to challenge the immune cells because this allowed us to perform the experiments throughout the year. Also, since DM is a perennial allergen its use did not affect seasonal variation. We hypothesized that 1) MSCs would suppress the proliferative response of DM-stimulated peripheral blood immune cells from allergic asthma subjects and, 2) Repeated exposure of low dose DM and MSCs to the immune cells of allergic asthma subjects would induce refractoriness to the allergen.
We were accurate in both points of the hypotheses. MSCs from an unrelated individual blocked the ability of DM to induce the proliferation of the immune cells. The MSCs also prevented the maturation of dendritic cells. MSCs induced an anergic response in DM-stimulated immune cells. A very interesting finding in the studies was the specificity of the MSCs. Specifically MSCs only suppressed the immune enhancing effect of DM but without any effect on the immune response of a recall antigen (tetanus toxoid). The paper that describes these findings was published in 2012. This paper supported the use of MSCs for allergic asthma patients and also showed promise for long-term tolerance to the allergen.
The suppressive effect of MSCs on allergic asthma cannot be extended to other airway inflammation. We performed follow-up studies with immune cells from allergic rhinitis and found that the MSCs worsened the proliferation of the immune cells (1). This occurred because the MSCs acted as antigen presenting cells, a property that was previously reported (2;3). Thus, the paper listed above showed a specific suppressor function for MSCs for induced asthma and also showed a tolerigenic cells is specific for allergic asthma.
MSCs and DM caused a decrease in mature dendritic cells (DCs) for allergic asthma subjects. The suppressive effect of MSCs was specific for DM since MSCs did not suppress challenges to Tetanus toxoid. The experimental evidence indicated that MSCs might be involved in resetting the immune response to make the cells more refractory to challenge with DM antigen.
Figure 1. T-cells from allergic rhinitis and allergic asthma were challenged with antigen. MSCs from an unrelated donor were added to the cultures. While MSCs suppressed the proliferation of T-cells from allergic asthma, they enhanced the proliferation from allergic rhinitis.
Figure 2: T-cells from allergic rhinitis and allergic asthma were challenged with antigen. MSCs from an unrelated donor were added to the cultures. While MSCs suppressed the proliferation of T-cells from allergic asthma, they enhanced the proliferation from allergic rhinitis.
- Desai MB, Gavrilova T, Liu J, Patel SA, Kartan S, Greco SJ et al. Pollen-induced antigen presentation by mesenchymal stem cells and T cells from allergic rhinitis. Clin Trans Immunol 2013; 2:e7.
- Chan JL, Tang KC, Patel AP, Bonilla LM, Pierobon N, Ponzio NM et al. Antigen-presenting property of mesenchymal stem cells occurs during a narrow window at low levels of interferon-γ¦. Blood 2006; 107(12):4817-24.
- Romieu-Mourez Rl, Francois Mr, Boivin MNl, Stagg J, Galipeau J. Regulation of MHC Class II Expression and Antigen Processing in Murine and Human Mesenchymal Stromal Cells by IFN-γ, TGF-β, and Cell Density. J Immunol 2007; 179(3):1549-58.
Pranela Rameshwar, Ph.D.
Department of Medicine-Hematology/Oncology
New Jersey Medical School – Rutgers
185 South Orange Ave, MSB, Room E-579
Newark, NJ 07103
Tel.: (973) 972-0625