Abstract
Autologous haematopoietic stem cell transplantation (AHSCT) is a therapeutic option for haematological malignancies, such as non-Hodgkin’s lymphoma (NHL), and more recently, for autoimmune diseases, such as treatment-refractory multiple sclerosis (MS). The immunological mechanisms underlying remission in MS patients following AHSCT likely involve an anti-inflammatory shift in the milieu of circulating cytokines. We hypothesised that immunological tolerance in MS patients post-AHSCT is reflected by an increase in anti-inflammatory cytokines and a suppression of proinflammatory cytokines in the patient blood. We investigated this hypothesis using a multiplex-ELISA assay to compare the concentrations of secreted cytokine in the peripheral blood of MS patients and NHL patients undergoing AHSCT. In MS patients, we detected significant reductions in proinflammatory T helper (Th)17 cytokines interleukin (IL)-17, IL-23, IL-1β, and IL-21, and Th1 cytokines interferon (IFN)γ and IL-12p70 in MS patients from day 8 to 24 months post-AHSCT. These changes were not observed in the NHL patients despite similar pre-conditioning treatment for AHSCT. Some proinflammatory cytokines show similar trends in both cohorts, such as IL-8 and tumour necrosis factor (TNF)-α, indicating a probable treatment-related AHSCT response. Anti-inflammatory cytokines (IL-10, IL-4, and IL-2) were only transiently reduced post-AHSCT, with only IL-10 exhibiting a significant surge at day 14 post-AHSCT. MS patients that relapsed post-AHSCT exhibited significantly elevated levels of IL-17 at 12 months post-AHSCT, unlike non-relapse patients which displayed sustained suppression of Th17 cytokines at all post-AHSCT timepoints up to 24 months. These findings suggest that suppression of Th17 cytokines is essential for the induction of long-term remission in MS patients following AHSCT.
Highlights
While autologous haematopoietic stem cell transplantation (AHSCT) is a successful treatment option for certain haematological malignancies [1,2,3], including non-Hodgkin’s lymphoma (NHL) [4, 5], it has been demonstrated to be an effective treatment for autoimmune diseases, such as multiple sclerosis (MS) when compared to other disease modifying therapies [6]
Proinflammatory cytokines are those that promote immune responses, such as those involved in T helper (Th) 17related immune responses, including interleukin (IL)-17 [17], IL23, IL-21, IL-6, IL-8 [18] and IL-1b [19], and those involved in Th1-related immunity, such as TNFa [20], IFNg [21] and IL12p70 [22]
T Cell-Associated Proinflammatory Cytokines Were Suppressed Within First 3 Months Post-AHSCT in MS Patients
Summary
While autologous haematopoietic stem cell transplantation (AHSCT) is a successful treatment option for certain haematological malignancies [1,2,3], including non-Hodgkin’s lymphoma (NHL) [4, 5], it has been demonstrated to be an effective treatment for autoimmune diseases, such as multiple sclerosis (MS) when compared to other disease modifying therapies [6]. It has been proposed that resetting of the immune balance and remission from CNS inflammation occurs through the removal of proinflammatory cells and the regeneration of immunoregulatory cells that are important in maintaining peripheral tolerance [9]. These cells are known to exert a myriad of immunoregulatory mechanisms, including the suppression of proinflammatory cytokine secretion [14,15,16]. Because Th1 responses are strongly correlated to MS pathogenesis [26, 27] and Th2 responses are associated with the dampening of MS activity [28], IL-4 is considered an anti-inflammatory cytokine in MS. IL-2 is involved in the proliferation and homeostasis of T cells [29] and can be considered anti-inflammatory due to its important role in the differentiation of immunoregulatory T regulatory cells (Tregs) [30,31,32]
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