Mycophenolate Mofetil Use Associates with Unique Biologic Changes in B Cell and T Regulatory Cell Pathways in SLE Patients

Samantha Slight-Webb¹, Rufei Lu², Krista M. Bean¹, Holden T. Maecker³, Paul J. Utz⁴, Joel M. Guthridge⁵ and Judith A. James⁶, ¹Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK, ²Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK, ³Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, ⁴Medicine, Stanford University School of Medicine, Stanford, CA, ⁵Arthritis & Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK, ⁶Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: Cell Signaling, CyTOF, cytokines, mycophenolate mofetil and systemic lupus erythematosus (SLE)

Session Information

Date: Monday, November 14, 2016

Title: Systemic Lupus Erythematosus – Human Etiology and Pathogenesis - Poster I

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose: The management of systemic lupus erythematosus (SLE) is complicated by a heterogeneous clinical presentation. Currently, mycophenolate mofetil (MMF) is a commonly used medication to treat major organ involvement in SLE, specifically in patients with lupus nephritis. The effectiveness of therapy is determined by clinical response, but the associated modulations of the lupus immune system in MMF responders are not known. This study assesses the systemic immunological changes that occur in SLE patients on MMF.

Methods: SLE patients currently receiving MMF (n=5) or not receiving MMF (n=15) were assessed in a cross-sectional design. Median disease activity and corticosteroid use was not significantly different between treatment groups. All SLE patients meet ACR criteria for classification of disease. Single-cell analysis of cell surface markers were completed by mass cytometry on PBMCs and cellular heterogeneity was visualized using viSNE in Cytobank. Further, phospho-specific flow cytometry was used to measure basal levels of pERK, pPLCγ2, pSTAT5 and p38 and expression following CD3/CD28 (TCR) and anti-IgG and IgM (BCR) stimulation. Soluble mediator levels in plasma were assessed using a 51-plex (Affymetrix) and by ELISA (eBioscience).

Results: Patients on MMF had significant reductions in transitional B cells (IgD+CD24+CD38+CD27-)(p=0.0143) and naïve B cells (IgD+CD38±CD24-CD27-)(p=0.0139) compared to SLE patients not taking this medication. In addition, activation of both monocytes (CD86+HLA-DR+)(p=0.0373) and B cells (CD86+CD19+CD20+) (p=0.05) were reduced in patients on MMF compared to non-MMF patients. MMF patients also had elevated levels of T cells that expressed CD161 (p=0.0488), a marker known to identify a subset of T regulatory cells, which significantly correlated with increased IL-2 levels in plasma. MMF patients also had reductions in a number of plasma cytokines and soluble mediators including chemokines (MIG, RANTES), growth factors (VEGF-A, SDF-1α, PDGF-BB) and the adhesion molecule VCAM-1 compared to non-MMF patients (p<0,05). Following BCR stimulation, patients on MMF had reduced levels of pSTAT5 (p=0.0367).

Conclusion: Our results indicate that SLE patients on MMF have reductions in both the frequency and activation status of antigen presenting cells and pro-inflammatory soluble mediator pathways, which is accompanied by an increase in T regulatory populations. Together these data provide potential insights to MMF mechanisms of action in SLE patients, define changes in MMF treated patients with suppressed disease activity and suggest immunologic changes that may be found in patients on this background medication.

Disclosure: S. Slight-Webb, None; R. Lu, None; K. M. Bean, None; H. T. Maecker, None; P. J. Utz, None; J. M. Guthridge, None; J. A. James, None.

To cite this abstract in AMA style:

Slight-Webb S, Lu R, Bean KM, Maecker HT, Utz PJ, Guthridge JM, James JA. Mycophenolate Mofetil Use Associates with Unique Biologic Changes in B Cell and T Regulatory Cell Pathways in SLE Patients [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/mycophenolate-mofetil-use-associates-with-unique-biologic-changes-in-b-cell-and-t-regulatory-cell-pathways-in-sle-patients/. Accessed .

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