The Challenges of Immunosuppressive Therapy in Organ Transplants
Organ transplant recipients face significant challenges due to the lifelong requirement for immunosuppressive therapy. These medications are essential to prevent the body’s immune system from rejecting the transplanted organ, but they come with severe drawbacks.
One of the most common and dangerous drawbacks of immunosuppressive agents is an increased risk of infection that the immune system would typically manage.[1] This requires patients to avoid many activities, interactions, and certain diets to prevent infection-related illnesses.
Additionally, long-term immunosuppressive therapy raises the risk of other health issues, including kidney, heart, and metabolic disorders.[2] Thus, there is a critical need for alternative treatments that enhance transplant tolerance without the associated risks of immunosuppression. Recent studies have shown that dendritic cells may hold the key to striking this critical balance in the patient’s immune system.
The Promise of Dendritic Cells in Transplant Tolerance
Recent medical research highlights the potential of donor immune cells to improve organ transplant tolerance. Among these immune cells, dendritic cells have emerged as a promising therapeutic target to reduce or eliminate the need for immunosuppressive therapy in organ transplant patients.
Dendritic cells, which are essential antigen-presenting cells, fall into three main categories: conventional, plasmacytoid, and monocyte-derived dendritic cells. Studies in humans and rodents have shown that dendritic cells can suppress graft-versus-host disease and experimentally induced autoimmune disorders.[3]
Human dendritic cells (DCs) are divided into three major categories: conventional (or myeloid) DCs, plasmacytoid DCs, and monocyte-derived DCs.
Dendritic Cells in Liver Transplantation
Liver transplantation presents significant challenges, with up to 30% of patients experiencing acute cellular rejection within the first year, increasing the risk of graft failure and mortality.[4] Conventional dendritic cells in hepatic homeostasis exhibit an immature phenotype with anti-inflammatory properties, poor T-cell stimulation, and tolerance.
Mouse studies revealed that injecting conventional hepatic dendritic cells into allogeneic recipients affected T-cell function by inducing interleukin (IL)-10 secretion, an anti-inflammatory cytokine that limits the host immune response to pathogens.
Liver-derived plasmacytoid dendritic cells also exhibit a lower capacity to activate T cells but stimulate IL-10−producing regulatory T cells. The role of monocyte-derived dendritic cells in organ transplantation is less understood, necessitating further studies. However, a 2014 study on human liver transplantation found increased IL-12 secretion, a pro-inflammatory cytokine, by monocyte-derived dendritic cells.[5]
Extending Kidney Allograft Survival with Dendritic Cells
Research in non-human primates demonstrated that a single infusion of donor dendritic cells could extend kidney allograft survival to nearly three times the median duration with minimal immunosuppression.
In a clinical trial involving autologous dendritic cells, a one-time infusion of non-pulsed autologous dendritic cells was administered one day before kidney transplantation, followed by standard immunosuppression.[6]
This approach was linked to a lower risk of viral infections, and several patients successfully discontinued immunosuppressive therapies by one year post-transplantation.
Future Directions and Ongoing Research
Using immature dendritic cells for transfer to organ transplant patients shows promise in enhancing tolerance and limiting graft rejection.
Due to the low abundance of dendritic cells in peripheral blood, they are primarily generated ex vivo from bone marrow precursors and peripheral blood monocytes cultured with substances that confer tolerogenic properties.
Ongoing studies aim to better understand the role of dendritic cells in organ transplantation and optimize their use in clinical settings.
Conclusion
Dendritic cells offer a promising avenue for improving organ transplant outcomes by enhancing tolerance and reducing reliance on immunosuppressive therapy.
Continued research and clinical trials are essential to fully realize the potential of dendritic cells in transplant medicine, potentially transforming the lives of transplant recipients by reducing complications and improving long-term health.
References
[1] Cleveland Clinic. “Immunosuppressants.” Accessed 25 June 2024. Available from: https://my.clevelandclinic.org.
[2] Ruiz R, Kirk AD. Long-Term Toxicity of Immunosuppressive Therapy. Transplantation of the Liver. 2015:1354–63. doi: 10.1016/B978-1-4557-0268-8.00097-X. Epub 2015 Apr 3. PMCID: PMC7152453.
[3] Yu H, Tian Y, Wang Y, Mineishi S, Zhang Y. Dendritic Cell Regulation of Graft-Vs.-Host Disease: Immunostimulation and Tolerance. Front Immunol. 2019 Feb 1;10:93. doi: 10.3389/fimmu.2019.00093. PMID: 30774630; PMCID: PMC6367268.
[4] Montano-Loza, A; Rodríguez-Perálvarez, M; Pageaux, G; Sanchez-Fueyo, A; Feng, S. Liver transplantation immunology: Immunosuppression, rejection, and immunomodulation. Journal of Hepatology, 2023, ISSN: 0168-8278, Vol: 78, Issue: 6, Page: 1199-1215. DOI: 10.1016/j.jhep.2023.01.030.
[5] Oberbarnscheidt M. H., Zeng Q., Li Q., Dai H., Williams A. L., Shlomchik W. D., et al. (2014). Non-self recognition by monocytes initiates allograft rejection. J. Clin. Investigation 124 (8), 3579–3589. 10.1172/JCI74370.
[6] Moreau, A; Kervella, D; Bouchet-Delbos, L; Braudeau, C; Limou, S; Josien, R; Cuturi, M; Blancho, G. A Phase I/IIa study of autologous tolerogenic dendritic cells immunotherapy in kidney transplant recipients, 2003. Kidney International, ISSN: 0085-2538, Vol: 103, Issue: 3, Page: 627-637. DOI: 10.1016/j.kint.2022.08.037.
