Depletion of B cells using anti-CD20 antibody treatment does not reset B cell tolerance
by Adam Burrack, PhD
We have previously covered the work of Thomas Tedder at Duke University, who studies B cells in the development of type 1 diabetes. As I described in this post from December 2015, one potential method to inhibit development of autoimmunity is to perturb interactions between autoreactive B cells and autoreactive T cells of the immune system. If these cell types do not productively interact, then autoantibodies will not be produced and perhaps T cells will not be instructed to attack insulin-producing beta cells. One approach to prevent these interactions is to deplete, or remove, one of these cell types through specific depletion approaches. This category of broad immune system suppression is hotly debated, both whether it will be effective and whether there will be severe side effects for patients. Nonetheless, B cell depletion by targeting the B cell surface protein CD20 with blocking antibodies (the commercial name of the antibody is rituximab), is an approach that has been used to treat type 1 diabetes, rheumatoid arthritis, and multiple sclerosis in the clinic, with varying degrees of success. In fact, Dr Tedder is an author on a recent publication in which B cell depletion with rituximab was used as a treatment for non-Hogkins lymphoma. In other words, short-term depletion of B cells is seen as a very promising treatment for several immune system-mediated diseases.
On the YOUglycemia blog, we have also described the research program of Kevan Herold at Yale, one of several researchers who has been involved in studies in which depletion of T cells of the immune system has appeared to slightly delay the onset of type 1 diabetes. Dr Herold is a member Type 1 Diabetes TrialNet, which conducted a recent study in which the B cells of patients with type 1 diabetes were monitored for the year following cessation of treatment with CD20 depleting antibodies. TrialNet is funded through both NIH, ADA, and JDRF and is a consortium of researchers who are working on clinical protocols to stop new-onset diabetes. More information, including the Mission Statement, are available here.
A recent TrialNet study in the prestigious Journal of Clinical Investigation, on which Kevan Herold is a co-author, studied the longer-term consequences of B cell depletion and found that B cell depletion does not reset B cell tolerance in patients with type 1 diabetes. TrialNet researchers characterized B cells in T1D subjects following rituximab treatment and demonstrated a transient decrease in total B cell numbers, but a continued high percentage of autoreactive B cells in blood of treated subjects. The researchers then tested whether these post-treatment autoreactive B cells were ‘new’ (recently developed) or ‘old’ (pre-existing and resisted depletion) and found that most autoreactive B cells remaining after B cell treatment were NEW B cells.
This suggests that transient B cell depletion does not reset any theoretical tolerance check-points in these patients, meaning that they continue to produce autoreactive B cells. This result calls into question the utility of B cell depletion to treat autoimmune conditions, including type 1 diabetes, and suggests that to change the situation we have to more specifically address the autoreactive cells, rather than simply removing B cells from the equation for a short time. From the overall failure of rituximab to reset B cell tolerance, my take-home is that global suppression of B cells is not the answer to prevent – or stop – autoimmunity.
In addition and very related, a recent paper from John Cambier’s laboratory at the University of Colorado—Anshcutz sheds light on the role insulin-specific B cells play in type 1 diabetes onset. In this cutting-edge technical report, researchers developed a reagent to track insulin-specific B cells in human patients, very similar technology to MHC-peptide tetramers for tracking specific T cell populations. Long story short this is not a tetramer, but is a method to specifically find insulin-reactive B cells in human peripheral blood. Dr Cambier collaborated with Peter Gottlieb at the Barbara Davis Center to track “anergic” (or non-responsive) insulin-specific B cells in people either at risk of type 1 diabetes, or right around the time of diagnosis with type 1 diabetes.
This team of researchers found a transient loss in B cell “anergy” around the time of diabetes onset, which did not last much more than 1 year following diabetes onset. In English, this means that insulin-specific B cells may have been participating in ramping up the immune response against insulin-producing beta cells around the time of diabetes onset. In other words, this work confirms that insulin-specific B cells are relevant to T cell activation and beta cell destruction. In contrast to my expectation as a scientist, the activation of insulin-specific B cells was transient – anergy in this set of B cells was only lost for a year. So, for example, since I personally I have had T1D for >30 years, this work suggests that insulin-specific B cells in my blood would now look ‘anergic’, or inactive, once again.
As an immunologist, this work highlights for me that the attack of beta cells leading to T1D is most likely to be the result of some specific activating signal in the pancreas that we don’t yet know. The evidence from the Cambier/Gottlieb paper is that the loss of regulation on B cell behavior is in a very narrow time window around the time of diabetes onset. The presence of autoreactive B cells (and T cells) is not necessarily normal, but they are not ‘always on’. In fact they appear to be ‘mostly off’ in terms of activation status. There is more to learn about how normal regulation of B and T cells of the immune system fails leading to overt autoimmunity.
Taken together, these reports highlight a need for a better understanding of B cell regulation, and the need for better methods to track specific B cell populations, both in mouse models of disease and in human patients. Since YOUglycemia is an action-based organization, here is my call to action. The non-scientists among us who care, passionately, about these types of studies can participate in accelerating this cutting-edge work by volunteering to be research subjects (for example through TrialNet), and/or through contributing financially to ADA, JDRF, or lobbying your Congress-people and Senators to expand NIH funding for these programs.