While organ transplant recipients receive life-long immunosuppressive medication to prevent their bodies mounting an immune response against donated organs, many still reject the organs. New research by the University of Chicago has shown that transplant recipients also have an immune reaction against commensal microbes in the organ. This adds to the immune reaction against the genetic makeup of tissue and reduces the effectiveness of immunosuppressive medicines.
The study, which was published today in Journal of Clinical InvestigationThis study also shows that the anti-microbial immune reaction can be triggered via immune cell memory from previous encounters with bacteria. This further complicates the body’s ability accept a lifesaving organ.
“Before, we thought the reason why transplanted organs in humans are less easily accepted than in sheltered laboratory animals is that humans can have immune memory responses that cross-react on the cells of the organ, and memory responses are more difficult to suppress with drugs than naïve responses,” said Maria-Luisa Alegre, MD, PhD, Professor of Medicine at UChicago and senior author of the study. “Now we know that it’s not just memory cells that recognize the organ that are the problem. But memory responses that recognize bacteria in an organ are also the problem.
Two different immune responses
The type of organ is crucial in determining the success rate of organ transplants. Lungs and small intestinales are notoriously hard to transplant and have shorter survival rates. Statistics show that after five years, 41% and 54%, respectively, of transplant recipients had rejected their grafts. This compares to organs such kidneys (just 27% rejection) as well as hearts (23%). One theory is that the lungs, intestines, and not the kidneys or hearts, are exposed microbes from both the air and the digestive system, and that organ recipients are mounting immune responses not just to those organs, but to them as well.
Alegre and her research team previously demonstrated that mice who received skin grafts colonized with it. Staphylococcus epidermidis – S. epiCommon bacteria found on the skin of humans is. S. epiThe graft was inflamed at low levels. The team wondered if the host had an additional immune reaction against the bacteria in graft, in addition to the more common “alloresponse,” which is a reaction to foreign cells in the tissue. If so, this could cause damage to the graft.
Alegre stated that the commensal bacteria found in the graft is different than the recipient’s commensal microbes. This means that the host might also consider these bacteria foreign. “We thought that maybe these two separate immune responses (host-versus-transplant and host-versus-bacteria) could work additively or synergistically to mount a more robust immune response against the graft and explain why the half-life of the organs that have microbes is shorter.”
Living with immune memory for a lifetime
The researchers used mice from UChicago’s gnotobiotic facility, which were carefully kept in sterile conditions and were not colonized with any microbes. To avoid an alloresponse the team transplanted skin taken from donors mice. The graft was initially colonized by the receiving mice, which elicited an immune response from their T cells. S. epiHowever, it did not when the graft was left sterile. Although the immune response to this injury did not cause severe damage to the skin grafts, it was still noticeable.
Alegre and her colleagues then tested whether prior immune exposure to commensal bacterium would cause more damage to a transplant containing similar bacteria. So they infected some recipients mice with the bacteria. S. epiBefore transplanting them, allow them to develop memory responses against the bacteria. The immune response to similar bacteria in the skin grafts was stronger and caused significant damage to the new tissue. This is because transplant patients are already exposed to many microbes over their entire lives through cuts, scrapes, and diet.
Most importantly, when they transplanted mice with skin grafts that were genetically different and colonized with bacteria — simulating the scenario like most human organ transplants — they saw that immunosuppressive drugs that prolonged transplant survival in naïve mice did not work in mice with anti-bacterial memory.
Alegre explained that patients who have had a transplant of a lung, intestine or other organ do not fare as well and must receive more immunosuppression than those who have transplanted sterile organs. You must address not only the anti-graft response, but also the bacteria response.