Hematopoietic SCT modulates gut inflammation in experimental inflammatory bowel disease

Abstract

Hematopoietic SCT (HSCT) and high-dose chemotherapy are being explored as therapy for various human refractory immune-mediated conditions, including inflammatory bowel diseases (IBD). Nevertheless, the exact immunological mechanisms by which the BM cells (BMCs) or immunosuppression provide remission from these diseases is not yet clear. In this work, we investigated the role of these therapies in the modulation of gut mucosal inflammation in an experimental model of IBD. Colitis was induced in mice by 2,4,6-trinitrobenzenesulfonic acid and after CY was administered (200 mg/kg) alone (CY group) or followed by BMCs infusion (HSCT group). Animals were followed for 60 days. Both HSCT and CY reduced the histopathological features of colitis significantly. Infused cells were localized in the gut, and a marked decrease of CD4 þ leukocytes in the inflammatory infiltrate on days þ 7 and þ 14 and of CD8 þ cells on day þ 7 was found in both treatments allied to impressive reduction of proinflammatory Th1 and Th17 cytokines. Although chemotherapy alone was the best treatment regarding the induction of immunosuppressive molecules, only HSCT resulted in increased survival rates compared with the control group. Our findings indicate that highdose CY followed by HSCT is effective in the modulation of mucosal immunity and in accelerating immune reconstitution after BMT, thus providing valuable tools to support the development and understanding of novel therapeutic strategies for IBD.

Bone Marrow Transplantation Helps Restore the Intestinal Mucosal Barrier after Total Body Irradiation in Mice

“…Both in animal models as well as in patients, BMCs have been reported to be involved in the healing process after intestinal injury (42). Therefore, to investigate the homing potential of BMCs to sites of radiation-induced injury, BMT mice were generated by using BMCs from GFP donor mice.…”

A single administration of human adipose tissue-derived mesenchymal stromal cells (MSC) induces durable and sustained long-term regulation of inflammatory response in experimental colitis

“…To ensure TNBS distribution throughout the colon, mice were held in a vertical position for 2 min after the enema [16]. The solution was administered through a 3·5-F catheter carefully inserted into the rectum until 4 cm proximal to the anal verge.…”

“…Finally, the sum of all values for each animal was calculated and plotted in the respective graphics [16]. This evaluation used a criterion score in which each signal exhibited by the animal corresponded to one point.…”

“…Accordingly, current available treatments are aimed at reducing inflammation in an attempt to avoid disease recurrence or to prolong clinical Clinical and Experimental Immunology ORIgInal aRTIClE remission periods. Preclinical studies have shown that the infusion of bone marrow cells (BMC) has successfully controlled experimental colitis [16,17], with the pretransplant conditioning of immunosuppressive therapies such as cyclophosphamide or total body irradiation. The partial inefficacy of pharmacological interventions and the unresponsiveness of some subjects has spurred clinical interest in developing other approaches for effectively controlling IBD.…”

“…However, many patients are refractory, so that surgery remains their only alternative [13]. The success of these therapies seem to be more correlated with immunosuppression than with transplantation per se, although prompt bone marrow reconstitution following immune ablation is essential to avoid receptor mortality [16,17]. Recently, transplantation of hematopoietic stem cells (HSCT) has become a therapeutic alternative for autoimmune or inflammatory diseases [14,15].…”