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B Cells: Tolerance, Accommodation, Regulation, Immunodeficiency and Therapy

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Javier Carbone, MD, PhD
Gregorio Maranon Hospital
Madrid, Spain

During the 35th Annual Meeting and Scientific Sessions of the International Society for Heart and Lung Transplantation from April 15th through April 18th, the contribution of B cells to accommodation, rejection or tolerance of the allograft was a topic of interest. Current understanding of the role of B cells in heart and lung transplantation is limited. What follows are some highlights from distinct sessions.

In a specific pre-meeting symposium (number 18) with focus in B cells in transplantation, Dr Esme Dijke opened the session with a great review of the role of B cells in the alloimmune response. Potential biomarkers related with donor specific IgG antibody secreting B cells (number, persistence and mutations of V region) should be taken into account. Dr Platt who originally described and named a phenomenon called "accommodation" reviewed the role of B cells in this phenomenon and in transplantation tolerance. Accommodation is important for the survival and function of organ transplants. It is interesting how the humoral immune response under certain conditions can modulate the damage to the allograft. There was an interesting discussion going on at the end of the session about what is better tolerance or accommodation. We donĀ“t know clearly yet which is the frontier between accommodation and tolerance. B cells have the capacity to control or regulate the immune response to the allograft. Dr. Paul Blair reviewed definitions of regulatory B cells in humans [CD20+CD24(hi)CD38(hi)IgM(hi)IgD(hi)CD1d(hi)]. These are IL10 producing B cells. These cells can inhibit disease activity or control the activation of other immune cells. He discussed about the challenges for regulatory B cell therapy in the future.

Targeting plasma cells in transplantation was the title of an interesting presentation made by Dr. Meena Clatworthy. Why do we care about acute antibody mediated rejection, chronic antibody mediated rejection and long lived plasma cells? These are a barrier for desensitization and for the therapy of antibody mediated rejection. Long lived plasma cells reside in multicomponent plasma cell niches. The role of chemokines, eosinophils, BAFF and APRIL in the niches and drugs that target plasma cells and distinct components in the niches were discussed.

Finally, Dr. Jignesh Patel presented data on desensitization protocols for sensitized patients awaiting heart transplantation including combined therapy with plasmapheresis and Bortezomib (abstract 61), terminal complement inhibition with eculizumab (abstract 62), or high dose IVIG combined with eculizumab. The potential role of prophylactic extracorporeal photopheresis and of Belatacept in the prevention of development of donor specific antibodies in heart transplantation were also discussed.

The regulation of the immune system is tightly connected to immune tolerance. B cells can also secrete cytokines and subsequently regulate immune responses mediated by T and innate cells. In the symposium The Future of Tolerance (number 12) Carla Baan reviewed the role of cytokines. IL-35 is a recently described cytokine that inhibits the proliferation of Th1 and Th17 cells. This cytokine is expressed by T regulatory cells, tolerogenic dendritic cells and also by regulatory B-cells and plasma cells.

B cell contribution to allograft dysfunction was explored in lung transplantation. In a study performed by Dr E. Vandermeulen and collaborators, CD20+ B cells were increased in patients with restrictive allograft syndrome and BOS (abstract 57).

Cardiac allograft vasculopathy (CAV) is a barrier for long term survival after heart transplantation. An interesting study performed by Dr C. Moore (abstract 248) characterized the clonal composition of B cell infiltrates in human cardiac allograft with CAV demonstrating the prevalence of polyreactive B cells in situ. Longitudinal B cell clone tracking was suggested from fixed paraffin sections.

The potential role of B-cells has also been investigated in ventricular assist device (VADs) users. VADs are associated with increased HLA antibody production in the bridge to transplant. Dr. M.H. Kwon and collaborators (abstract 605) observed that patients who had strong HLA antibody production had an increase in median levels of B cell activating factor (BAFF) as compared with nonsensitized patients.

Immunosuppressive therapies can lead to a secondary B-cell immunodeficiency state. One of the biomarkers of this state is hypogammaglobulinemia. Dr. R.S. Traister (abstract 367) presented data of a prospective study in lung recipients to evaluate the relationship between hypogammaglobulinemia and clinical outcomes. Among 133 lung recipients, those with hypogammaglobulinemia at 3 months after transplantation were at risk for developing recurrent pneumonia and increased mortality at 1 year. Hypogammaglobulinemia was a component of an immunological score to identify heart recipients at risk of infection in a prospective study presented by Dr. E. Sarmiento and collaborators (abstract 317). The same group presented data of a pilot clinical trial in which the replacement of hypogammaglobulinemia with IVIG was associated with a decreased risk of infection in heart transplantation (abstract 316).

Thus, the information presented during the meeting emphasizes that B cells contribute in multiple ways to allograft dysfunction, rejection, but also to regulation and tolerance, and suggest a complex balance that exists between the positive and negative regulatory functions of B cells after transplantation. ■

Disclosure Statement: The author has no conflicts of interest to disclose.

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