Monday, April 27, 2015

Topic Discussion: Do B regulatory cells exist and do they help in transplant tolerance?

Recently, David Rothstein from Pittsburg gave an amazing grand rounds on B regulatory cells in NYSN in New York. Here are some notes on what I learnt.

B cells can influence T cell differentiation but B cells are effector cells themselves.  B cells also are responsible for antibody production. Do B regulatory cells exist?

Koichi et al showed in an elegant manner that certain subset of B cells in mice produce IL-10 and they might have regulatory function. In addition, IL-10 production was restricted to this CD1dhiCD5+ B cell subset, with IL-10 production diminished in Cd19−/− mice. Thereby, CD1dhiCD5+ B cells represent a unique subset of potent regulatory B cells per authors in that study.

Ding et al in JCI showed that B cells that had the IL-10 production also had a TIM-1 marker.  What is TIM-1.  T cell Ig domain and mucin domain protein 1 (TIM-1) is a costimulatory molecule that regulates immune responses by modulating CD4+ T cell effector differentiation. TIM-1 was expressed by a large majority of IL-10–expressing regulatory B cells in all major B cell subpopulations, including transitional, marginal zone, and follicular B cells, as well as the B cell population characterized as CD1dhiCD5+.  They showed that with a  low-affinity TIM-1–specific antibody that normally promotes tolerance in mice, actually accelerated (T cell–mediated) immune responsiveness in the absence of B cells. TIM-1+ B cells that had IL-10 expression  could directly transfer allograft tolerance.  What is possible is that TIM-1 is an inclusive marker for IL-10+ Bregs.

Could these be the cells that induce tolerance in transplant patients?

Yeung et al answered this question in mice. B cells that express a mutant form of TIM-1 lacking the mucin domain (TIM-1Δmucin) are unable to produce IL-10 in response to specific ligation with anti-TIM-1. TIM-1Δmucin mice also exhibit accelerated allograft rejection, which appears to be due in part to their defect in both  baseline and induced IL-10+ Bregs, since a single transfer of WT TIM-1+ B cells can restore long-term graft survival.
That’s in mice studies. It is impossible to measure TIM-1 in humans as percentage of these cells might be just <1%.

No one is aware of a disease entity that exists that is a Breg deficiency. IPEX syndrome is a Treg deficiency syndrome. One study has looked at kidney transplant human samples in JASN and using Breg data. 

Cherukuri etal. examined the cytokine profiles of human samples and found that subsets of CD24(hi)CD38(hi) transitional B cells (TrBs), CD24(hi)CD27(+) memory B cells, and naïve B cells express IL-10 and the proinflammatory cytokine TNF-α simultaneously. TrBs had the highest IL-10/TNF-α ratio and suppressed proinflammatory helper T cell 1 (Th1) cytokine expression by autologous T cells in vitro more potently than memory B cells did, despite similar IL-10 expression. What was important was the  ratio of IL-10/TNF-α expression, a measure of cytokine polarization, as an indicator of regulatory function than IL-10 expression alone. Indeed, compared with TrB cells from patients with stable kidney graft function, TrBs from patients with graft rejection displayed similar IL-10 expression levels but increased TNF-α expression (i.e., reduced IL-10/TNF-α ratio), did not inhibit in vitro expression of Th1 cytokines by T cells, and abnormally suppressed expression of Th2 cytokines. In patients with graft dysfunction, a low IL-10/TNF-α ratio in TrBs associated with poor graft outcomes after 3 years of follow-up. So, B cell-mediated immune regulation is best characterized by the cytokine polarization profile, a finding that was confirmed in renal transplant patients.  This is an amazing start. Hope to see more of this work to help us figure out the holy grail of transplant- tolerance!!

Interestingly, in a study done in NEJM where rituximab was used to deplete B cells as induction agent in transplantation, there were more rejection episodes in that arm.  Perhaps there was too much B reg depletion?   

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