Abstract
Aplastic Anemia (AA) is an immune-mediated form of acquired bone marrow failure (BMF), which is life-threatening in its severe form (SAA). Fundamental pathological features of AA include development and expansion of auto-reactive effector T cells, effector T cell-mediated apoptosis of all hematopoietic cells (including progenitors and hematopoietic stem cells (HSCs)), BM aplasia, pancytopenia, depletion of HSCs, and severe reduction and functional impairment of regulatory T cells (Tregs).
Current standard treatments for AA include: (1) immuno-suppressive therapy (IST) with cyclosporine A (CyA) and anti-thymocyte globulin (ATG) which targets all T cells, and (2) allogeneic or matched unrelated donor BM transplant. While IST remains a standard treatment modality, it is not very effective in treating already ongoing and relapsed AA or SAA. There is really no effective therapy for patients with refractory and relapsed AA who are ineligible for BMT.
Among different pathophysiological features of AA, IST targets only the effector T cells, and is much more effective in the early than later stages of AA. Moreover, the combination of IST with other immunosuppressive agents (mycophenolate mofetil, sirolimus etc.) or growth factors does not improve the response or survival of AA patients. Since the incidence of AA is on the rise, there is an urgent need for more efficient new therapies that can attenuate the progression and severity of AA in patients with refractory and relapsed AA who are waiting for or are not candidates for BMT.
The complex immune and hematological pathophysiology of AA requires new multipurpose treatment approaches. Accumulating evidence shows that β2 integrin CD11b/CD18 (Mac-1) negatively regulates T cell responses and activation, attenuates inflammation, and facilitates the maintenance of tolerance to self-antigens. For example, activated Mac-1 significantly reduces the T cell-activating capacity of dendritic cells (DCs), represses DC cross-priming of cytotoxic T cells, negatively regulates NK cell activation and function, suppresses differentiation of Th17 T cells which are associated with AA and other autoimmune diseases, ameliorates experimental autoimmune hepatitis, and negatively regulates BCR signaling and maintains autoreactive B cell tolerance. For that reason, Mac-1 is an attractive molecular target for new immune-modulating therapies of autoimmune diseases.
Using the clinically relevant mouse SAA model we have evaluated the therapeutic efficacy of Leukadherins (LA1-LA3), novel small molecule agonists and activators of Mac-1, as a novel multipurpose immunosuppressive and anti-inflammatory approach to treat AA. The present studies have demonstrated that administration of LA1 safely and significantly (1) suppresses expansion of effector T cells, (2) decreases effector T cell-mediated apoptosis of target BM cells, (2) reduces BM aplasia, (3) minimalizes the loss of HSCs and progenitors, and (4) attenuates the severity of SAA. Furthermore, prolonged treatment of developing SAA with LA1 has therapeutic effects since it not only attenuates the progression and severity of SAA, but also converts otherwise fatal SAA into a survivable disease in mouse SAA models.
To begin to address mechanism for these findings we found that LA1 treatment significantly reduces the antigen presenting capacity and T cell activating capacity of DCs. Importantly, in vivo LA1 treatment significantly increases the population of regulatory T cells (Tregs) which may also contribute to the above effects of LA1 on SAA.
Simultaneous targeting of multiple pathophysiological features of AA underscores the clinically relevant potential of LA1 treatment as a novel promising multi-target immunosuppressive therapy that can safely and efficiently attenuate the severity of AA and reduce the need for BMT. We are also further evaluating the potential of LA1 treatment combined with IST or in vivo Treg expansion approaches (low dose rIL-2 therapy) to safely and more effectively attenuate the progression and severity of AA in pre-clinical mouse SAA models. These studies will provide an important platform for further translational and clinical testing of LAs as: (1) New therapy to manage ongoing AA in patients who are not responding to IST and are not candidates for BMT, (2) New therapy for relapsed AA, and/or (3) Adjuvant therapy for AA patients who are undergoing IST and are awaiting BM transplant.
Disclosures
Levy: Allergan: Consultancy.
T cell-intrinsic S1PR1 regulates endogenous effector T-cell egress dynamics from lymph nodes during infection