Second in a two-part series on transplant tolerance. (See part one.)
Our immune system has two major kinds of T cells. T helper cells, also known as effector T cells, tend to rev up our immune responses, while T regulatory cells tend to suppress or downregulate them. Last week we reported that bolstering populations of T regulatory cells might help people tolerate organ transplants better. A new study turned its focus to T helper cells, and found that an imbalance of these cells causes an exaggerated immune response that may also contribute to transplant rejection.
The study also showed, in mice and in human cells in a dish, that the immune imbalance can be potentially reversed pharmacologically. Findings were published yesterday in the Journal of Clinical Investigation.
A skewed immune response
Paolo Fiorina, MD, PhD, of Boston Children’s Hospital, Francesca D’Addio, MD, PhD, of the University of Milan, and their colleagues studied 747 patients who had received a heart transplant, drawing on two Italian studies (AIRT-Bologna and NIT-Bergamo) and an American study (CTOT-05). Most of the patients underwent genetic profiling, and 413 had clinical and immunologic data available.
Genetic profiling revealed that patients who had a mutation in the P2X7R gene were more likely than the others to develop immune events and to reject their transplant. They were also more likely to have major cardiac events within 10 years of transplant and increased coronary artery maximal intimal thickness, an indicator of coronary artery disease.
Immune profiling of blood samples showed that people with these poor outcomes tended to have an altered balance of two kinds of T helper cells. Populations of Th2 cells were reduced, while Th17 cells, which provoke an especially strong inflammatory immune response, were increased.
The P2X7R/NLRP3 axis
The researchers then delved further into P2X7R’s function. They found that the P2X7R protein controls the development of T helper cells into different types by interacting with another protein, NLRP3. Mutations disrupting P2X7R skewed the immune system toward producing an excess of Th17 cells after a transplant.
“Our data suggest that carriers of the mutant P2X7R allele may have a fragile immune system that is at risk of developing a ‘hyper-Th17 syndrome’ when they receive a transplant or when their immune system is stimulated by other means, such as infections, inflammation or tissue damage,” says D’Addio, the study’s first author. “This pathway may also favor the development of immune-mediated disorders such as autoimmune diabetes.”
When P2X7R was deleted in mice, the researchers saw the same pattern as in the patients with P2X7R mutations. After heart transplant, Th2 cell production was reduced and Th17 cell production was increased, leading to early graft rejection.
“We have discovered that a P2X7R/NLRP3 axis exists to control T-helper cell fate in the context of immune activation and that it is dysfunctional when the P2X7R gene is mutated,” says Fiorina, the study’s first author and a researcher in Boston Children’s Division of Nephrology.
Stimulating P2X7R in human T helper cells in a dish led to activation of NLRP3, the team found. Normally, NLRP3 goes to the cell nucleus to stimulate production of Th2 cells. But when P2X7R was mutated, NLRP3 couldn’t reach the nucleus. This, in turn, reduced the Th2 cell pool and led to an increase in Th17 cells.
A treatment to prevent graft rejection… and more?
Finally, the team tried neutralizing Th17 cells in their mouse model by using an antibody to block IL-17, the chemical signal (cytokine) it produces. Results were good: The animals’ P2X7R/NLRP3 dysfunction was near-normalized, graft survival was significantly prolonged and there was less evidence of post-transplant coronary artery disease. IL-17 blockade also reduced Th17 “skewing” of human T cells in a dish.
Further study will be needed to determine whether dysfunction of the P2X7R/NLRP3 axis contributes to immune disorders in the general population.
“As we have now demonstrated that this axis exists, we have to identify those individuals at risk and establish a therapeutic approach to neutralize it,” says Fiorina. “Two percent of us carry this mutation and may be predisposed to develop unexpected immune diseases.”
Fiorina is now investigating additional small molecules and recombinant proteins that may prevent the excessive immune activation seen in this study. Such approaches could prove relevant not only for transplantation, but also for autoimmune diseases like type 1 diabetes, he says.
The study was supported by EFSD/Sanofi European Research Programme, an American Heart Association (AHA) Grant-in-Aid.
Co-authors were Andrea Vergani, Moufida Ben Nasr, Vera Usuelli, Roberto Bassi, Sergio Dellepiane and Sara Tezza of Boston Children’s Hospital’s Division of Nephrology; Luciano Potena, Laura Borgese and Francesco Grigioni of Bologna S. Orsola University Hospital Bologna; Anna Maestroni of the International Center for T1D, University of Milan; Domenico Corradi, of the University of Parma, Italy; Kaifeng Liu and Gary Visner of the Pulmonary Division and Transplant Research Program, Boston Children’s Hospital; Maria Iascone and Attilio Iacovoni of the Ospedale Papa Giovanni XXIII, Bergamo, Italy; Bassett El Essawy of the University of Cairo, Egypt; Sirano Dhe Paganon of the Dana Farber Cancer Institute; Randall Starling of the Cleveland Clinic; Franco Folli of the University of Milan; Reza Abdi and Anil Chandraker of Brigham and Women’s Hospital; Mohamed Sayegh of the American University of Beirut; Peter Heeger of Mount Sinai Hospital, New York; and Gian Vincenzo Zuccotti of the International Center for T1D, University of Milan, and Buzzi Children’s Hospital, Milan.
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