Wednesday, 4 December 2013

T cell growth linked to autoimmunities after Alemtuzumab

Jones JL, Thompson SA, Loh P, Davies JL, Tuohy OC, Curry AJ, Azzopardi L, Hill-Cawthorne G, Fahey MT, Compston A, Coles AJ. Human autoimmunity after lymphocyte depletion is caused by homeostatic T-cell proliferation. Proc Natl Acad Sci U S A. 2013 Nov 26. [Epub ahead of print]


The association between lymphopaenia and autoimmunity is recognized, but the underlying mechanisms are poorly understood and have not been studied systematically in humans. People with multiple sclerosis treated with the lymphocyte-depleting monoclonal antibody alemtuzumab offer a unique opportunity to study this phenomenon; one in three people develops clinical autoimmunity, and one in three people develops asymptomatic autoantibodies after treatment. Here, we show that T-cell recovery after alemtuzumab is driven by homeostatic proliferation, leading to the generation of chronically activated (CD28-CD57+), highly proliferative (Ki67+), oligoclonal, memory-like CD4 and CD8 T cells (CD197-CD45RA- or CD197-CD45RA+) capable of producing proinflammatory cytokines. Individuals who develop autoimmunity after treatment are no more lymphopaenic than their non-autoimmune counterparts, but they show reduced thymopoiesis and generate a more restricted T-cell repertoire. Taken together, these findings demonstrate that homeostatic proliferation drives lymphopaenia-associated autoimmunity in humans.
It is well known that an adverse effect of alemtuzumab is antibody mediated autoimmunities, and others develop autoantibodies. This study suggests that the autoimmunities develop after a repopulation of T cells, but with a restricted set of specificities, but it does not say how to stop these developing


4 comments:

  1. "Individuals who develop autoimmunity after treatment are no more lymphopaenic than their non-autoimmune counterparts, but they show reduced thymopoiesis and generate a more restricted T-cell repertoire."

    Does this statement enable a more accurate identifaction of those with a higher risk factor for auto-immune side effects post-Alemtuzumab? If my monthly bloods show lower than average thymopoiesis and a more 'restricted T-cell repetoire' (I imagine I'd need to read the full paper to know what this looks like in real teams on a CBC result), that would presumably mean I need to be extra-vigilant for the potential auto-immune complications?

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    1. I suspect this is a research tool at present and am not sure what will be monitored save to say testing or the presence of autoimmunity.

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  2. Selected lymphocyte depletion with alemtuzumab leads to homeostatic t-cell repopulation and autoimmunity. Seems that tolerance induction following alemtuzumab treatment may generate a less restrictive t-cell population reactive to autoantibodies. Could the reconstitution of t-cells be influenced by the existing inflammatory damage and debris that persists in MS lesions? An earlier post using the train wreck analogy, proposed by Dr. Stys, suggested recruitment of lymphocytes to clear the debris. Lymphocytes were a consequence not the cause.

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    1. Lymphocytes produce autoantibodies and that is the problem with the autoimmunities after alemtuumab. This may need T cell help.

      As T cells regenerate their responsiveness can be influenced.

      In terms of Train wreck lymphocytes are not designed to remove debris this is the job of macrophages, they may recruit monocytes to cause this to be done

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