Medical Professional Publications

Improving Allogeneic Bone Marrow Transplant Outcomes

(From the January 2015 Issue of PediatricsOnline)

Graft-versus-host disease, a complication in which the T cells of a bone marrow donor attack tissues in the transplant recipient, is among the leading causes of death in children receiving allogeneic bone marrow transplants. In a multi-institutional project, clinician-researchers in the Host Defense and Blood and Marrow Transplant Programs at Nationwide Children’s Hospital studied the effects of human marrow-derived mesenchymal stromal cells (MSCs) on graft-versus-host disease in mice. While the stromal cell injections did not inhibit the therapeutic anti-leukemia activity of donor T cells, they did help slow graft-versus-host disease progression and decrease its severity. The research is the first compelling evidence that mesenchymal stromal cells impede donor T-cells from attacking tissues in the recipient while preserving the donor T-cells’ ability to fight the recipient’s cancer.

In allogeneic bone marrow transplants, blood-forming stem cells from a closely matched donor are injected into the transplant recipient after chemotherapy or radiation, which eradicate cancer cells in the recipient but also destroy the bone marrow in young cancer patients. In children with leukemia, the immune cells from the donor help fight any remaining cancer and allow the recipient to produce their own healthy blood cells.

Although bone marrow transplants can cure cancer, the therapy itself carries many risks, including an attack of the donor cells on the cells of the recipient, or acute graft-versus-host disease (GvHD). Acute GvHD afflicts up to one-third of pediatric patients receiving allogeneic bone marrow transplantation. GvHD is also responsible for about one in every five deaths following allogeneic bone marrow transplants.

“The need for better prevention and therapy for acute GvHD is readily apparent,” says the study’s first author, BMT specialist and Director of the Host Defense Program Jeffery J. Auletta, MD. “Current therapies for acute GvHD target T-cell activation, function and cytokine production, which delays donor-derived immune recovery and increases the risk for life-threatening infection. New approaches and novel agents to prevent the development of acute GvHD are critically needed.”

Human MSCs have been safely administered to BMT patients in attempts to reduce the occurrence of GvHD. However, enthusiasm for using MSCs in the allogeneic BMT setting has been tempered by discouraging results in clinical trials. According to Dr. Auletta, this likely reflects the field’s lack of understanding for how these cells function after they are infused into patients.

In this study, which was published in the journal Stem Cells, human MSCs were injected one and four days after BMT in a clinically relevant mouse model of allogeneic transplantation. Novel imaging was then used to show that human MSCs migrated within 72 hours to secondary lymph node organs, like the spleen, which have established roles in promoting GvHD. Once in the secondary lymphoid organs, human MSCs decreased T-cell proliferation, thereby elucidating an underlying in vivo mechanism for how the MSCs might attenuate acute GvHD.

Figure 1.
Cryoimaging technology provides single-cell detection anywhere in the mouse, giving unique quantitative analyses of fluorescently labeled cells. Here, the cryoimaging indicates biodistribution and colocalization of human MSCs (red dots) and alloreactive T-cells (green dots) 48 hours after BMT and 24 hours after MSC injection. The blue arrow indicates the location of the spleen. This image first appeared in Stem Cells in connection with the article discussed herein. Used with permission.

Most importantly, the study showed that human MSCs significantly lessened the severity of acute GvHD onset without compromising graft-versus-leukemia (GvL) activity. Together, the findings suggest that human MSCs may potentially separate GvHD from GvL responses in the allogeneic BMT recipient, Dr. Auletta says.

Figure 2.
Administration of the MSCs visibly reduced GvHD-related tissue damage in the animal liver and gut samples compared to allogeneic transplants without MSC injections, even approaching the health of tissue samples from animals receiving BMTs from identical twins, or syngeneic transplants. This image first appeared in Stem Cells in connection with the article discussed herein. Used with permission.

“Our findings indicate that human MSCs preserve donor immune cell responses directed against leukemia cells and diminish responses directed against tissues of the transplant recipient. In so doing, MSCs could diminish morbidity and mortality associated with GvHD, without compromising beneficial donor-derived GvL response needed to cure malignant disease,” says Dr. Auletta, who also is an associate professor of Pediatrics at The Ohio State University College of Medicine. “Understanding the behavior and impact of MSCs may improve outcomes in allogeneic bone marrow transplant recipients, ideally by reducing complication rates without negatively impacting the transplants’ efficacy against cancer.”

Dr. Auletta and the study’s co-authors hope that the results from this study can be used to direct future work investigating how human MSCs modify immune response in the body. Ultimately, this could generalize the application of allogeneic BMT to other diseases by decreasing the risk for acute GvHD currently associated with its use.

Citation
Auletta JJ, Eid SK, Wuttisarnwattana P, Silva I, Metheny L, Keller MD, Guardia-Wolff R, Liu C, Wang F, Bowen T, Lee Z, Solchaga LA, Ganguly S, Tyler M, Wilson DL, Cooke KR. Human mesenchymal stromal cells attenuate graft-versus-host disease and maintain graft-versus-leukemia activity following experimental allogeneic bone marrow transplantation. Stem Cells. 2014 Oct 21. [Epub ahead of print]

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