Comparative study of clinical grade human tolerogenic dendritic cells

M Naranjo-Gómez, D Raïch-Regué, C Oñate, L Grau-López, C Ramo-Tello, R Pujol-Borrell, E Martínez-Cáceres, Francesc E Borràs, M Naranjo-Gómez, D Raïch-Regué, C Oñate, L Grau-López, C Ramo-Tello, R Pujol-Borrell, E Martínez-Cáceres, Francesc E Borràs

Abstract

Background: The use of tolerogenic DCs is a promising therapeutic strategy for transplantation and autoimmune disorders. Immunomodulatory DCs are primarily generated from monocytes (MDDCs) for in vitro experiments following protocols that fail to fulfil the strict regulatory rules of clinically applicable products. Here, we compared the efficacy of three different tolerance-inducing agents, dexamethasone, rapamycin and vitamin D3, on DC biology using GMP (Good Manufacturing Practice) or clinical grade reagents with the aim of defining their use for human cell therapy.

Methods: Tolerogenic MDDCs were generated by adding tolerogenic agents prior to the induction of maturation using TNF-α, IL-β and PGE2. We evaluated the effects of each agent on viability, efficiency of differentiation, phenotype, cytokine secretion and stability, the stimulatory capacity of tol-DCs and the T-cell profiles induced.

Results: Differences relevant to therapeutic applicability were observed with the cellular products that were obtained. VitD3-induced tol-DCs exhibited a slightly reduced viability and yield compared to Dexa-and Rapa-tol-DCs. Phenotypically, while Dexa-and VitD3-tol-DCs were similar to immature DCs, Rapa-tol-DCs were not distinguishable from mature DCs. In addition, only Dexa-and moderately VitD3-tol-DCs exhibited IL-10 production. Interestingly, in all cases, the cytokine secretion profiles of tol-DCs were not modified by a subsequent TLR stimulation with LPS, indicating that all products had stable phenotypes. Functionally, clearly reduced alloantigen T cell proliferation was induced by tol-DCs obtained using any of these agent. Also, total interferon-gamma (IFN-γ) secretion by T cells stimulated with allogeneic tol-DCs was reduced in all three cases, but only T cells co-cultured with Rapa-tol-DCs showed impaired intracellular IFN-γ production. In addition, Rapa-DCs promoted CD4+ CD127 low/negative CD25high and Foxp3+ T cells.

Conclusions: Our results demonstrate contrasting influences of different clinical-grade pharmacological agents on human tol-DC generation. This should be taken into account for decisions on the use of a specific agent for the appropriate cellular therapy in the context of a particular disease.

Figures

Figure 1
Figure 1
Survival of tol-DCs after clinical protocol differentiation. (A) Viability of MDDCs with or without immunomodulatory treatment after 6 days of differentiation. Plots are representative of 5 independent experiments. (B) Surviving cells are annexin V and 7AAD negative cells. (C) Yield obtained calculated as the number of MDDCs obtained from the initial number of monocytes that were cultured (n = 5). (paired t-test. * p ≤ 0.05; ** p ≤ 0.001; ***≤ 0.0001).
Figure 2
Figure 2
Dexa-and VitD3-DCs exhibit a semi-mature phenotype as compared with Mat-DCs. (A) DC expression of maturation-associated markers of immature DCs (Im-DCs), mature DCs (Mat-DCs) and tol-DCs. Surface expression of CD86-FITC, CD83-APC and HLA-DR-APCH7 staining on MDDCs. Each histogram is representative of 15 independent experiments. Isotype controls are shown in grey. (B) Results are mean fluorescence intensities from n = 11 cultures in the presence of Dexa, n = 15 cultures with Rapa-DCs and n = 11 cultures with VitD3-DCs. (paired t-test. * p ≤ 0.05; ** p ≤ 0.001; ***≤ 0.0001).
Figure 3
Figure 3
Tolerogenic dendritic cells (tol-DCs) exhibit an anti-inflammatory cytokine profile and stable phenotype. (A) IL-10 release by DCs in the presence or absence of immunomodulatory agents (Dexa, Rapa or VitD3) was measured after 48 h stimulation with a maturation cocktail. Supernatants were harvested and analysed for IL-10 production by MILLIPLEX (Dexa: n = 6; Rapa: n = 7 and VitD3: n = 11). (B) Stability of tol-DCs was evaluated after culture for 24 h in XVIVO medium containing LPS (without immunomodulatory agent). IL-10 and IL-23 production was determined for all DC conditions (with or without LPS). (n = 4. Statistical significance derived from a paired t-test. * p ≤ 0.05).
Figure 4
Figure 4
Tolerogenic dendritic cells (tol-DCs) suppress T cell proliferation without apoptosis induction. (A and B) Allogeneic T cells were stimulated with tol-DCs and compared for proliferation with stimulation by Mat-DCs and Im-DCs in mixed-lymphocyte reactions. Compared to Mat-DCs, tol-DCs potently inhibited allogeneic T cell proliferation at a level similar to Im-DCs (Dexa: n = 7; Rapa: n = 10; and Vit D3: n = 10). (C) Viability results (%Annexin V and 7AAD negative) for T cells co-cultured with different cellular products (n = 4).
Figure 5
Figure 5
Decreased production and secretion of IFN-γ by T lymphocytes stimulated with tol-DCs. Proliferating T lymphocytes were obtained from allostimulatory cultures. The production of interferon (IFN)-γ was measured by intracellular staining after restimulating the cells with PMA+Io in the presence of brefeldin for 5 h. (A) First row (i) shows gating CD3+ cells. The second row plots (ii) indicate the proportion of total IFN-γ producing cells. Third row (iii) shows the percentages of cells that responded to allostimulation (CFSElow) and produced IFN-γ. The numbers inside the plots indicate the percentage of cells in each quadrant or boxes (a representative experiment). (B) Summary of the results of the total intracellular IFN-γ (Upper Left, UL) production with Dexa-(n = 4), Rapa-(n = 7) and Vit D3 (n = 7) activated cultures relative to Mat-DCs (taken as 100% production). (C) Percentage of IFN-γ producing T cells that responded to allostimulation (CFSElow CD3+ cells). Each symbol represents an individual sample. Significant differences are indicated (** p < 0,001; paired t-test).
Figure 6
Figure 6
Rapa-DCs promote CD4+CD25hiCD127lowFoxP3+ induction from blast T cells. After 6 days of culture without re-stimulation and any supplemental cytokines, cell sizes were evaluated by FACS by plotting forward scatter (FSC) versus side scatter (SSC) parameters. Small (solid line) non-blast cells and large (dotted line) blast cells are circled. (A) Phenotype of T cells as CD4+, Foxp3+ and CD25+ with low or null CD127 expression. One of 6 representative experiments is shown. (B) Summary of percentages of T cells in non-blast (left) and blast (right) cells. (* p ≤ 0.05, n = 6, paired t-test).

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