A novel approach to reduce graft-vs-host disease

Monika R, PSG College of Technology, Coimbatore

Stem cell transplantation (SCT) has emerged as the treatment of choice for most people suffering from disorders of the hematopoietic and immune systems or cancer. Each year, 12,000-15,000 allogeneic SCTs are estimated worldwide, with a continuing growth rate of 10-20% per year. 

Allogeneic SCT is a medical procedure in the haematology and oncology field, where the patients receive stem cells from the person who is more related to them, often a sibling. The advantage of allogeneic SCT is that the donor stem cells make their immune cells competent. This system can help destroy any cancer cells that may remain following high-dose treatment in the host.

Allogenic SCTs performed in people with lymphohematopoietic malignancies, immunodeficiencies, and marrow failure syndromes. For each of these diseases, the primary goal of allogeneic bone marrow transplantation (allo-BMT) is to replace the recipient’s lymphohematopoietic system with a fully competent one from the donor. 

Transfer of hematopoiesis can get easily accomplished, but the successful transfer of a fully functional immune system remains a significant problem. The extent and the rate of immune reconstitution are influenced highly by the presence or absence of graft-vs-host disease (GVHD). Positive outcomes following allo-BMT, limited by life-threatening complication-GVHD.

Graft-vs-host disease (GVHD)

GVHD is an immune response that involves donor T cells and the genetically disparate recipient. GVH’s response intensifies as a result of this seemingly simple immune interaction. Chronic GVHD has remained elusive as it continues to be the leading cause of late death without relapse, while the prevention and treatment of acute GVHD have improved over the past 20 years. The beneficial effect of graft-vs.-leukaemia/lymphoma (GVL) on survival was disproportionate due to increased mortality without relapse associated with infections and organ failure during chronic GVHD. Not surprisingly, chronic GVHD has a significant negative impact on survival, which has not improved significantly over the last 30 years.

Strategies to prevent or treat GVHD

Donor T-cell-mediated Graft-vs-host disease (GVHD) continues to be the principal complication of allo-BMT, along with graft rejection, leukemic relapse, and opportunistic infections. Standard immunosuppressive strategies to prevent/treat GVHD involve depleting T-cells of donor stem cells. This leads to other risk factors due to the slow immunological reconstitution in the recipient. (i.e.) Depletion of the donor T-cell to reduce the incidence of GVHD, worsen post-transplant immunodeficiency. Therefore, since the prevention of GVHD converges at immunosuppression, it results in the clinical complications of infection and recurrence of malignancy. Thus, the GVHD and immune reconstitution are inextricably linked together in allogeneic SCT biology.

Thus, the key to successful allo-BMT lies in the ability to ameliorate Graft-vs-host disease (GVHD) while still promoting the beneficial T-cell responses of graft-vs.-leukaemia (GVL) effects, enhanced stem cell engraftment, and the capacity to resist infections. The challenge for the future is to develop new therapies that can enhance the competence of the transferred immune system against both infection and malignancy without worsening GVHD.

Leland Metheny, Assistant Professor (Medicine) at University Hospitals Seidman Cancer Center, Cleveland, US, with other researchers, has researched a new method for a successful allo-BMT by nullifying the development of systemic GVHD. This research has just got published in the journal Stem cells.

“GVHD is a side-effect of allogeneic stem cell transplant which is difficult to treat, whereas most therapies involve significant immunosuppression. MAPC can offer an alternative to those therapies as treatment for GVHD,” said Leland Metheny. 

MAPC – Novel approach

Human bone marrow-derived, multipotent, and adult progenitor cells (MAPC) represent a subset of regenerative stromal cells (RSCs). They potentially differentiate into cells from each of the three germ layers and expand broadly ex-vivo while retaining their pluripotency. MAPC cells also possess tissue regenerative and immunomodulatory properties.

Saada Eid from the Department of Pediatrics, Case Western Reserve University, Cleveland, Ohio, and the co-author of this study, stated: “We used a clinically relevant murine model to elucidate the in-vivo immunomodulatory effects of MAPC on donor T-cell responses after allo-BMT. Murine allo-BMT models have helped define mechanisms contributing to stem cell engraftment, immune reconstitution, GVHD, and GvL activity”.

They observed potent immune-modulatory activity following administration of MAPCs within the first week of experimental allo-BMT. These effects were characterized by significant reductions in donor-derived T-cell activation and expansion, systemic inflammation, and GVHD severity while preserving potent cytotoxic anti-leukemic activity, both in vitro and in vivo.

“This strategy is also non-cross reactive with immunosuppressive approaches to prevent or treat GVHD,” said Leland Metheny. Importantly, their research illuminated the biodistribution of human MAPC after injection, the optimal dose and timing of administration, and possible mechanisms of action underlying the regulatory effects of MAPC therapy following allo-BMT.

Future concern

This research, which explores human MAPC treatment following allo-BMT, may offer critical insights to optimizing their therapeutic potential in future clinical trials. But the biodistribution of MAPCs and the specific mechanisms which may have beneficial effects are not yet fully understood. Given the immunomodulatory effects of MAPCs on T-cell activation, careful monitoring for leukemic relapse and opportunistic infections should be concerned in any forthcoming studies.

Also read: Is heritability of the gut microbiota possible?

Source:

Auletta, J. J., Eid, S. K., Wuttisarnwattana, P., Silva, I., Metheny, L., Keller, M. D., Guardia-Wolff, R., Liu, C., Wang, F., Bowen, T., Lee, Z., Solchaga, L. A., Ganguly, S., Tyler, M., Wilson, D. L., & Cooke, K. R. (2015). Human mesenchymal stromal cells attenuate graft-versus-host disease and maintain graft-versus-leukemia activity following experimental allogeneic bone marrow transplantation: Human mscs reduce gvhd and maintain gvl activity. STEM CELLS, 33(2), 601–614. https://doi.org/10.1002/stem.1867

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About the author: Monika Raman is an undergraduate student pursuing her final year B. Tech in Biotechnology. She is an enthusiastic Biotech student aspiring for an opportunity to develop skills and grow professionally in the research field. Extremely motivated and possess strong interpersonal skills.