Northwestern Medicine scientists have discovered how a subset of immune cells are essential for successful organ transplantation acceptance and that therapeutically targeting them may improve long-term survival post-transplant, according to a recent study published in The Journal of Clinical Investigation.
Heart transplantation is critical for patients who have end stage heart failure, the most advanced stage of heart failure in which the heart is too weak to be improved with treatment. Although patient survival rates a year after organ transplantation have improved over time, improvements in long-term survival have remained stagnant.
After an organ transplant, patients typically receive immunosuppressant medications to prevent their immune system from attacking the new organ. However, these medications also make patients more susceptible to infection, cancer and can cause damage to other organs, including the kidneys and liver.
In the current study, the investigators aimed to better understand the role of a subset of immune cells called type 1 conventional dendritic cells (cDC1) in organ transplantation and how those cells could be therapeutically targeted to help prevent organ transplant rejection.
“This study looked at the ways we can co-opt natural functions of the immune system to be more tolerant or accepting of a foreign antigen or a foreign particle like a transplant to then accept the organ and need either less immunosuppressant medication or no medication at all,” said Samantha Schroth, an MD/PhD candidate in the Medical Scientist Training Program (MSTP) and lead author of the study.
The scientists used a multi-pronged approach to study models of heart transplantation using mice that were engineered to be deficient in cDC1s — dendritic cells that help the immune system recognize foreign antigens.
“These cells are almost like the teacher of the immune system,” Schroth said. “They present foreign particles to the other immune cells and educate those cells on if this is something worth attacking or not.”
From their analysis, the scientists discovered that cDC1-deficient mice would reject the heart transplant faster than mice that weren’t cDC1-deficient. They also found that cDC1-deficiency led to a decrease in regulatory T-cells (Tregs), which normally helps prevent the immune system from becoming overactive.
“We didn’t see this robust increase in regulatory T-cells like we saw in a mouse that had its full immune system, which made us think the cDC1 cell must be important for educating the regulatory T-cells,” Schroth said.
By closely analyzing the cDC1 cells in the mice, the investigators found an increase in the surface protein TGF beta 1, which helps control cell growth and proliferation and, in this case, helps cDC1 cells engage with Tregs. To validate this finding, the scientist created a knockout mouse model lacking TGF beta 1 on cDC1s and found that these mice also rejected the heart transplant.
The findings may inform new targeted strategies to preserve solid organ allografts and improve long-term survival.
“Could we use some targeted therapeutics to able to influence metabolism of a cell in a targeted way, like with a nanoparticle, that then specifically targets a dendritic cell or a cDC1 cell? Would you be able to functionally change the way that the cell is then interacting with T-cells and regulatory T-cells?” Schroth asked.
Schroth said moving forward, her team will further investigate the molecular properties of other subsets of dendritic cells and determine if they could also be promising therapeutic targets for improving the immune systems response to organ transplantation.
“The value of understanding the basic mechanisms that are happening in the complex reality of the immune system is so critical to be able to translate this to human medicine,” Schroth said.
Edward Benjamin Thorp, PhD, the Frederick Robert Zeit Professor of Pathology, was senior author of the study.
Co-authors of the study include Kristofor Glinton, PhD, research assistant professor of Medicine in the Division of Cardiology; Jesse Davidson, MD, assistant professor of Surgery in the Division of Organ Transplantation; Navdeep Chandel, PhD, the David W. Cugell, MD, Professor of Medicine in the Division of Pulmonary and Critical Care; and Samuel Weinberg, ’19 MD, ’19 PhD, assistant professor of Pathology in the Division of Experimental Pathology.
Thorp, Weinberg and Chandel are members of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
This work was supposed by the National Institutes of Health grants 1F30HL162456-01A1, 1T32GM144295, R35HL177401, R01HL175893, and AHA24SFRNPCN1289611 and T32AI007476; an American Heart Association pre-doctoral fellowship (903851); the Sidney and Bess Eisenberg Memorial Fund; and the Dr. Michael M. Abecassis Transplant Innovation Endowment Grant from the Comprehensive Transplant Center (CTC).
