by Renée de Pooter, PhD
Staff scientist in the Department of Pathology
What do Natalie Cole, Dick Cheney, and Jim Nabors have in common?
Like a growing number of Americans—33,600 in 2016—they received life-saving organ transplants. When vital organs like the lungs, heart, liver, or kidneys are destroyed by disease or genetic conditions, organ transplantation is the only cure. Many of these organs come from people who sign their organ donor cards, in the hopes that even in tragedy they might be able to save someone else’s life. Marisa Alegre, MD, PhD, and her team at the University of Chicago are trying to learn how to prolong survival for both the transplanted organ and the recipient, to get the most benefit from this final, amazing gift of life.
Surgical recovery is only the beginning for transplant recipients, because the life-saving organ comes from another person and their bodies know it. Our immune systems evolved to protect us from infections, but some microbes can burrow inside our cells to avoid detection. To leave clues about where these stealthy invaders are hiding, infected cells leave “breadcrumbs” on their surfaces, by-products of what the invaders are making inside. Like drug-sniffing dogs on a raid, immune cells hunt down these clues in the body’s nooks and crannies. If they find something unfamiliar, they howl and send the DEA agents, the T cells, into defensive action.
It’s a great system, except when someone receives an organ transplant.
Then the immune system attacks the foreign cells, thinking it’s fighting a massive infection. To pacify the immune system, organ recipients face a lifetime of immunosuppressant drugs. Unfortunately, this stupefies their T cells and leaves the recipient vulnerable to infection and cancer.
In rare cases, the immune system and the transplanted tissue reach a truce. In these “tolerant” individuals, the new organ survives without the immunosuppressive drugs and the immune system still protects against disease. Clinicians usually find these outliers by accident: the patient stops taking his or her immunosuppressants for medical or financial reasons and yet still survives, perhaps even thrives.
Many researchers, including Alegre, took note of these lucky unicorns. They reasoned that if we better understood how these patients became and stayed tolerant, we might be able to improve outcomes for many more transplant recipients.
Several years ago, the teams of Alegre and Anita Chong, PhD, showed that severe bacterial infections could cause transplant rejection in previously tolerant mice. Then, they set out to test how the microbiome – the collection of bacteria that live on the mice – affects transplant survival.
First, they treated mice with antibiotics. This didn’t wipe out the entire microbiome, but killed off all the antibiotic-sensitive members. They found that treating both donor and recipient nearly doubled the survival time of the transplant.
Next they looked at germ-free mice, special experimental animals born and raised in bacteria-free bubbles—an exceptionally expensive but irreplaceably useful laboratory technique. As with antibiotic-treated mice, foreign tissue transplanted in germ-free mice lasted longer than usual.
The team then exploited an icky but valuable characteristic of mice: they eat poop. Alegre’s team fed the germ-free mice the poop of mice with a normal microbiome: a fecal transplant. Germ-free mice that were fed normal mouse poop rejected the organ grafts as quickly as the normal mice. But when the germ-free mice got poop from antibiotic-treated normal mice, they rejected the organ graft as slowly as their brethren who remained bacteria-free. It appears that at least one of the normal components of the mouse’s microbiome—one sensitive to the antibiotics—was causing the immune system to reject the new organ faster.
This work suggests that we might be able to increase transplant tolerance in humans by treating them with specific antibiotics. And if we can discover the exact bacteria causing the rejection, we might be able to use a short-term antibiotic targeted very directly at eradicating the trouble-makers, perhaps even in the case of organs harvested after a donor’s death.
Weeding out the microbial agitators while leaving most of the patients’ microbiome intact may allow doctors to limit the immunosuppressants prescribed and help keep their patients healthy for a new life with a new organ.
