Background/Purpose: While the ASSET clinical trial (placebo-controlled blinded trial of abatacept) in patients with diffuse cutaneous systemic sclerosis (dcSSc) did not meet its primary endpoint of statistically significant improvement in the modified Rodnan skin score (mRSS), patients with early disease (≤ 5 years) and inflammatory subtype, showed meaningful clinical improvement compared with the placebo group1-2. We also found that SSc patients have increased percentages of CD4+ T cells and B cells, but a lower percentage of CD8+ T cells compared to healthy control subjects. Importantly, a robust expansion of CD319+ T cells was seen among the CD4+ cells, whereas they were barely detectable in healthy subjects3. We now know that these CD4+CD319+ (also known as SLAM-F7+) cells are highly cytotoxic and are a dominant T cell population in perivascular lymphocytic infiltrates in SSc skin. In this new study, we analyzed the effects of abatacept on both CD4+CD319+ and CD8+CD319+ cells in peripheral blood of 67 dcSSc patients enrolled in the ASSET trial.

Methods: All SSc patients were participants in the ASSET study where longitudinal blood was available. Lymphocyte subsets were characterized by multi-parameter flow cytometry of peripheral blood mononuclear cells at times 0, 1, 3 and 6 months of the ASSET study. Patients were stratified according to their pattern of gene expression on baseline skin biopsies, into three predefined distinct subgroups: inflammatory, fibroproliferative and normal-like. Cytotoxic CD319+ T cells and production of the cytokines INF-γ, IL-4 and IL-17 were measured by intracellular flow cytometry, in both unstimulated cells and following T cell activation in overnight cultures.

Results: A profound decrease of CD319+ T cells was seen within CD4+ cells and CD8+ cells at 6 months (p=0.0313 and p=0.0212 respectively) in patients treated with abatacept compared with placebo (Figure 1). Frequencies of IL-4+ cells within CD4+CD319+ and CD8+CD319+ cells were significantly reduced at 3 months (p=0.0072 and p=0.0381 respectively) but significance was not reached at 6 months. Reduction of dual IL-4/IFN-γ producing CD319+ cells was observed in abatacept treated patients at 6 months, but not in the placebo group (Figure 2). Among normal-like, proliferative and inflammatory SSc subtypes, we found a statistically significant decrease in IL-4 producing CD4+CD319+ cells in the proliferative subtype at 3 months when compared to placebo (Figure 3).

Conclusion: Abatacept has shown promise as a therapy in a subset of early dcSSc patients, emphasizing the need to explore its effects on abnormal and potentially pathogenic immune cell subsets. Here, we demonstrate that abatacept effectively reduces CD319+T cell numbers systemically and also decreases the proportion of CD4+CD319+ cells that are engaged in IL-4 and IL-4/IFN-γ production. Given the fact that CD319 is aberrantly expressed on both CD4+ and CD8+T cells in dcSSc patients, targeting these cells might hold great promise for therapeutic adjustment of lymphocyte balance and function in dcSSc.

Figure 1. Abatacept reduces cytotoxic CD4+CD319+ and CD8+CD319+ cell populations in systemic sclerosis. (A): CD4+CD319+ and (B): CD8+CD319+ cells were examined at baseline and 6 months after abatacept or placebo treatment. Patients treated with abatacept showed a significant decrease of CD319+ T cells within CD4+ cells and CD8+ (*p < 0.05, paired t-test). (C) and (D): Data presented in boxplots.

Figure 2. Abatacept reduces the percentage of IL-4/IFN-γ producing CD4+CD319+ and CD8+CD319+ cells in systemic sclerosis. Frequencies of IFN-γ, IL-4 and IL-17 cells within CD4+CD319+ and CD8+CD319+ cells were assessed 1, 3 and 6 months after treatment. Similarly, dual IFN-γ/IL-4, IFN-γ/IL-17 and IL-4/IL-17 production was also assessed at the same time-points. (A): Reduction of dual IL-4/IFN-γ producing CD4+ CD319+ cells was observed in abatacept treated patients at 6 months (p < 0.05), but not in the placebo group (n.s.). (B): A decrease in IL-4/IFN-γ producing CD8+ CD319+ cells was seen in the abatacept group, although differences did not reach statistical significance (p=0.0128). Similarly, abatacept lowered IL-17/IFN-γ production in CD8+ CD319+ cells (p=0.0005), but not in CD4+ CD319+ cells at 6 months (C and D). Other analyses of single cytokine production and dual IL-4/IL-17 production did not reach statistical significance (data not shown). Data was normalized to baseline (*p < 0.05, paired t-test).

Figure 3. Abatacept decreases IL-4 producing CD4+CD319+ and CD8+CD319+ cells in proliferative subtype patients. (A): IL-4 producing CD4+CD319+ and CD8+CD319+ cells were statistically decreased in the abatacept group at 3 months (p=0.0072). When comparing subtypes of SSc based on their gene signature, we observed a statistically significant reduction in IL-4-producing CD4+CD319+ cells after among the proliferative subtype (p=0.0314). (B): Abatacept decreases IL-4 producing CD8+CD319+ cells (p=0.0381). A reduction was also seen when comparing abatacept vs placebo in the proliferative subgroup at 3 months. Significant differences between abatacept vs placebo were assessed by a paired-t test. Differences between normal-like, proliferative and inflammatory subsets were assessed using one-way ANOVA with Tukey’s multiple comparison test (*p < 0.05).

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/abatacept-reduces-cd319-slam-f7-cytotoxic-t-cells-and-cytokine-production-in-systemic-sclerosis/