Background/Purpose:

Systemic lupus erythematosus (SLE) patients exhibit T-cell dysfunction which can be reversed by blockade of the mechanistic target of rapamycin (mTOR) with therapeutic efficacy (Nat. Rev. Rheumatol. 12:169-182, 2016; Lancet, 391:1186-1196, 2018). Since mTOR is a key controller of mammalian lifespan (Nature 460:392-395, 2009; Science 326:140-144, 2009), we examined the relationship of immune senescence to rapamycin-responsive pro-inflammatory lineage skewing in SLE.

Methods:

838 immunometabolic parameters were assessed by flow cytometry (Lancet, 391:1186-1196, 2018) in 84 SLE patients (44.3±1.4 years of age; mean±SE; range 18-71) having active disease and unresponsive or intolerant to conventional medications, but unexposed to treatment with rapamycin. Disease activity was characterized by SLEDAI (10.1±0.7), BILAG (27.8±1.3), and prednisone use (5.3±1.4). Control samples for biomarker studies were obtained from 84 healthy controls (HC) and matched for patients’ age (45.0±1.4 years of age; range 20-63), gender, and ethnicity for each visit. Rapamycin (sirolimus) was started at 2 mg/day with dosage adjusted to tolerance and 6-15 ng/ml through levels in 40 of these SLE patients over 12 months (ClinicalTrials.gov number NCT00779194). The number (n) of patients available for each assay is indicated. Statistical analyses were performed with GraphPad (San Diego, CA); changes at 2-tailed p<0.05 were considered significant for hypothesis testing.

Results:

Patients’ age did not correlate with SLEDAI, BILAG, or prednisone dosage. Aging occurred with increased mitochondrial transmembrane potential or mitochondrial hyperpolarization (MHP) and increased mitochondrial mass in all T cells, increased CD4/CD8 ratio, depletion of CD45RA⁺ naïve and expansion of CD45RO⁺ memory CD8⁺ T cells both in SLE and HC subjects. Expression of CD98 and activation of mTOR complex 1 (mTORC1) in CD4⁺ T cells was enhanced and CD4⁺CD25⁺FoxP3⁺ Tregs were expanded of HCs only, while mTORC1 activity was selectively increased in CD8 T cells and CD4^–CD8^–CD3⁺ double-negative (DN) CD27^–CD197^– T cells and CD8⁺CD62L^–CD197^– effector-memory T cells were only expanded in SLE patients with aging. Rapamycin expanded CD4⁺CD45RO⁺ memory T cells, CD8⁺CD62L^–CD197^– effector-memory T cells, and CD8⁺FoxP3+ Tregs irrespective of age, while it preferentially reduced nitric oxide production, MHP, and mitochondrial mass in DN T cells, expanded CD4⁺FoxP3⁺ Tregs, IFNγ-producing CD4⁺ and CD8⁺ T cells, and CD19⁺ B cells in younger SLE patients (37.0±2.7 years of age; n=14). Rapamycin preferentially reduced the production of IL-4 and IL-17 by DN and CD8⁺ T cells in older SLE patients (57.6±1.5 years of age; n=14).

Conclusion:

Age-related metabolic changes underlie pro-inflammatory lineage specification and may contribute to clinical efficacy of mTOR blockade in SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/age-related-metabolic-changes-underlie-pro-inflammatory-lineage-specification-and-contribute-to-therapeutic-responsiveness-to-mechanistic-target-of-rapamycin-blockade-in-sle/