A patient’s lymph nodes may offer an ideal transplantation site for cell- or tissue-based therapies against a range of diseases that currently necessitate whole-organ transplantation, or the transfer and engraftment of cells into already damaged tissue, scientists claim. Studies in mice by University of Pittsburgh scientists have shown that healthy lymph nodes will support engraftment of diverse cell types such as hepatocytes, thymic tissue, and pancreatic islet cells, and that the transplanted cells generate functional surrogate organs in the lymph nodes that can reverse the pathology of diseases such as liver failure and diabetes.
The human body contains over 500 lymph nodes, and the concept that these sites can provide a foster home for a wide range of cell types is supported by the fact multiple cancer cell types will often metastasise first to lymph nodes, where they can continue to grow and proliferate. The latest work by Eric Lagasse, Ph.D., and colleagues now suggests that this hospitable environment could be harnessed for regenerative therapy.
The team tested to see whether the lymph node environment could also support the engraftment and function of different cell types for cell therapy application. For the first set of experiments, the researchers transferred syngeneic hepatocytes into a single jejuna lymph node of a mouse model of lethal metabolic liver failure. Twelve weeks later they found that the cells had engrafted in the lymph node and effectively generated a functional ectopic liver that rescued the recipient animals from lethal liver failure. In fact, in the Fah-/- mouse model used, hepatocytes transplanted into just one jejunal lymph node developed into tissue representing about 70% of the mass of a mouse liver. Encouragingly, the technique was equally effective when other lymph nodes were used as the transplantation site.
Projecting the future use of this approach for treating liver disease in humans, the investigators say the overall aim wouldn’t necessarily be to replace the patient’s liver, rather the ectopic tissue would hopefully provide enough cell mass to stabilize liver function until an organ donor is found, or help the patient’s own liver regenerate.
For the second set of experiments the team transplanted thymuses taken from healthy newborn mice into jejuna lymph nodes of athymic (BALB/c) nude mice. A month later the recipient animals were producing CD4+ and CD8+ cells from their own bone marrow, and these immune cells were still being generated 10 months later. Notably, when the ectopic thymus tissue was analyzed, it was found that the transplanted cells had organized into thymic medullary and cortical epithelia, and that the T cell population induced a full complement of regulatory, naive, central memory, and effector T cells that could mount T cell-mediated immune responses to skin allografts and tumor xenografts.
In a third set of studies, the investigators harvested pancreatic islets from C57BL/6 mice and transplanted these into the jejuna lymph nodes of C57BL/6 wild type mice treated with streptozotocin, a compound that induces diabetes. Encouragingly, the transplanted islets expressed C-peptide and glucagon, which are indicators of pancreatic β-cell and α-cell function. Importantly, the transplanted islets functioned to restore glucose concentrations in the recipient animals to normal levels within six weeks, and, in one animal evaluated, normoglycemia was maintained for at least six months after lymph node transplantation.
Describing their work in Nature Biotechnology, the Pittsburgh investigators say that to their knowledge this is the first time that lymph node evaluation as a site for functional cellular transplantation has been reported. “By directly injecting the lymph node with hepatocytes, thymuses, or pancreatic islets, we demonstrate engraftment of the donor cells and subsequent organ function,” they state. “This new approach of using the lymph node as an in vivo bioreactor in which to regenerate functional organs may be beneficial to the field of regenerative medicine.”