Alemtuzumab it isn’t just problems with B cell Autoimmunities.

A
Alemtzumab induces CD8 mediated autoimmunity. 

Is it Shock, Horror, Probe! or time for more reading on how T cells
repopulate after depletion

Ruck T, Pfeuffer S, Schulte-Mecklenbeck A, Gross CC, Lindner M, Metze D, Ehrchen J, Sondermann W, Pul R, Kleinschnitz C, Wiendl H, Meuth SG, Klotz L. Vitiligo after alemtuzumab treatment: Secondary autoimmunity is not all about B cells. Neurology. 2018 Nov 7. pii: 10.1212/WNL.0000000000006648. 

OBJECTIVE:To report 3 patients with relapsing-remitting multiple sclerosis (RRMS) showing vitiligo after treatment with alemtuzumab.
METHODS:Retrospective case series including flow cytometric analyses and T-cell receptor (TCR) sequencing of peripheral blood mononuclear cells.
RESULTS:We describe 3 cases of alemtuzumab-treated patients with RRMS developing vitiligo 52, 18, and 14 months after alemtuzumab initiation. Histopathology shows loss of epidermal pigmentation with absence of melanocytes and interface dermatitis with CD8+ T-cell infiltration. Also compatible with pathophysiologic concepts of vitiligo, peripheral blood mononuclear cells of one patient showed high proportions of CD8+ T cells with an activated (human leukocyte antigen-DR+), memory (CD45RO+), and type 1 cytokine (interferon-γ + tumor necrosis factor-α) phenotype at vitiligo onset compared to a control cohort of alemtuzumab-treated patients with RRMS (n = 30). Of note, analysis of CD8 TCR repertoire in this patient revealed a highly increased clonality and reduced repertoire diversity compared to healthy controls and treatment-naive patients with RRMS. We observed a predominance of single clones at baseline in this patient and alemtuzumab treatment did not substantially affect the proportions of most abundant clones over time.
CONCLUSION:The 3 cases represent a detailed description of vitiligo as a T-cell-mediated secondary autoimmune disease following alemtuzumab treatment. The prevailing concept of unleashed B-cell responses might therefore not cover all facets of alemtuzumab-related secondary autoimmunity. Mechanistic studies, especially on TCR repertoire, might help clarify the underlying mechanisms.

No sooner have we come up with an idea about how B cell autoimmunities may develop after autoimmunties, other neuros are trying to make us look elsewhere with the inference that it is driving CD8 T cell mediated autoimmunity. Whilst the B cell idea is one heck of a hypothesis when it comes to  B cells in that you regenerate immature, potentially self-reactive, B cell populations in the absence of T cell regulation and antibody induced autoimmunities occur once T cell help returns.




Do we now have to think how CD8 autoimmunity occurs?


First things first. Is it Alemtuzumab causing Vitiligo?

I don’t know, so I’ll keep an open mind, but if so how is it doing it?
Alemtuzumab is supposed to deplete CD8 T cells out of sight, but they do recover quicker than CD4 T cells and are back to normal levels within 12 months. So for 2 people the onset of disease would be within this range. But the Vitiligo was occurring at 14 months in one person, so 2 months after infusion. Therefore, the first question is, Is alemtuzumab not doing its job?


We know that some people do not deplete or deplete poorly and one of the people was relapsing on alemtuzumab and rituximab, so they were not doing a good job at controlling MS.


We are not told if there was CD8 depletion but as they were in skin lesions  two months after alemtuzumab the answer has got to be that alemtuzumab was not effective.


Were antibodies related to Vitiligo antigens present? We do not know except that there were no CD20 B cells in lesions when looked for.

Is it just chance that Vitiligo occurred in MS too? “Vitiligo is sometimes associated with autoimmune diseases, including MS.

We know that alemtuzumab is not 100% effective in MS, so have the people simply become exposed a new autoimmunity. 


It is funny that CD8 is highlighted as a problem in vitiligo, but it is not considered as the main problem in MS, yet we see that CD8 infiltrates are the dominant lymphocyte subsets in MS. Therefore is it simply the mechanism that allows MS to return occurring in people with a propensity to have MS and Vitiligo?.

Vitiligo is a long-term  skin condition characterized by patches of the skin losing their pigment. The patches of skin affected become white and usually have sharp margins. The hair from the skin may also become white.The exact cause of vitiligo is unknown. It is believed to be due to  genetic susceptibility, that is triggered by an environmental factor such that an autoimmune disease occurs. This results in the destruction of skin pigment cells.

The TYR gene encodes the protein tyrosinase, which is not a component of the immune system, but is an enzyme of the melanocyte that catalyzes melanin biosynthesis, and a major autoantigen in generalized vitiligo

Studies revealing that melanocyte-specific antibodies and cytotoxic T cells have been detected in the peripheral blood of vitiligo patients supports the autoimmune hypothesis. The cytotoxicity of CD8+ T cells to melanocytes is considered to make a key contribution to the pathogenesis of non-segmental vitiligo. The autoimmune response is suggested to trigger the vitiligo but is not the main factor that affects the extent and duration of the disease”

Study of cutaneous lymphocytes in vitiligo revealed that infiltration of CD8+T cells occurs surrounding the vitiligo lesions.


There is no mention of whether these people had melanocyte-related antibody.


In this study they look at the CD8 TCR repertoire in this patient revealed a highly increased clonality and reduced repertoire diversity compared to healthy controls and treatment-naive patients with RRMS.  This suggests that they have found a clone expanded by disease. They should now be able to find the antigen to which they react. It could be a vitiligo cause or it could be anti-viral response. They observed single clones and limited diversity. 

This is not surprising because is what happens with alemtuzumab..and HSCT and probably cladribine, you just need to read the papers and understand that following depletion, T cells recover by stereotyped behaviours and in this case the important route is by homeostatic proliferation. (The non-specific expansion of T cell populations within a whole or part of an organism to reach to a total number of T cells which will then remain stable over time in the absence of an external stimulus).


Xu H, Bendersky VA, Brennan TV, Espinosa JR, Kirk AD. IL-7 receptor heterogeneity as a mechanism for repertoire change during postdepletional homeostatic proliferation and its relation to costimulation blockade-resistant rejection. Am J Transplant. 2018 Mar;18(3):720-730.

Zwang NA, Turka LA. Homeostatic expansion as a barrier to lymphocyte depletion strategies. Curr Opin Organ Transplant. 2014 Aug;19(4):357-62.

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 Dec 10;110(50):20200-5


In the paper it was mentioned that Interleukin-21 may drive this. However in other papers it is IL-7 (IL-7R is one of the first Non-major histocompatibility complex genes associated with MS Susceptibility) and IL-15.

They “observed a predominance of single clones at baseline in this patient and alemtuzumab treatment did not substantially affect the proportions of most abundant clones over time”.

However, as cells expand to fill the space, clones will get expanded.

As you can see above the idea that homeostatic proliferation can cause autoimmunity is not new. This was the idea about the CAM-THY trial, which failed. Although we predicted this would fail, it was said by Prof Coles (Last week At the Limits) that the idea to use thymocyte stimulation with a drug, as shown in Monkeys, did not work in humans and implied it reduced diversity not increased it..


So did it make things worse? Apparently not, but the trial was stopped years early suggesting something was wrong.

A limited diverisity of CD8 clones that were common before HSCT has also been seen.


Muraro PA, Robins H, Malhotra S, Howell M, Phippard D, Desmarais C, de Paula Alves Sousa A, Griffith LM, Lim N, Nash RA, Turka LA.T cell repertoire following autologous stem cell transplantation for multiple sclerosis. J Clin Invest. 2014 Mar;124:1168-72. We found that HSCT has distinctive effects on CD4+ and CD8+ T cell repertoires. In CD4+ T cells, dominant TCR clones present before treatment were undetectable following reconstitution, and patients largely developed a new repertoire. In contrast, dominant CD8+ clones were not effectively removed, and the reconstituted CD8+ T cell repertoire was created by clonal expansion of cells present before treatment. Importantly, patients who failed to respond to treatment had less diversity in their T cell repertoire early during the reconstitution process


So what’s the difference between atemtuzumab and HSCT.  Were they the same surviving clones. Is it a virus that they react to?

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6 comments

  • "Mechanisms for development of secondary AD may be related to loss of peripheral tolerance after conditioning (eg, by deletion of regulatory cells),8 proliferation of autoreactive cells after HSCT by homeostatic expansion,17 failure of negative selection during de novo thymic ontogenesis of T lymphocytes,18 or accumulation of mutations during increased proliferation of lymphocytes after HSCT"

    Alemtuzumab fault?

    Mechanisms for development of secondary AD may be related to loss of peripheral tolerance after conditioning (eg, by deletion of regulatory cells),8 proliferation of autoreactive cells after HSCT by homeostatic expansion,17 failure of negative selection during de novo thymic ontogenesis of T lymphocytes,18 or accumulation of mutations during increased proliferation of lymphocytes after HSCT

    In conclusion, patients with SLE, younger age at HSCT, or receiving severe T cell-depleting conditioning (ATG, alemtuzumab, CD34+ selection) need close monitoring for secondary AD after autologous HSCT. Further prospective studies analyzing patients treated for primary AD or for other hematologic indications will help to delineate the various patterns and mechanisms of autoimmunity before and after HSCT.

    http://www.bloodjournal.org/content/118/6/1693?sso-checked=true

  • ". Among the 155 patients, the frequency of secondary autoimmune complications was 16.0% with alemtuzumab (4/25), 1.9% for ATG (2/102), and 0% for conditioning regimens without lympho-depleting antibodies (0/28)—a difference that was found to be significantly higher with alemtuzumab exposure (P = .011). In contrast, sex, type of ATG used, and CD34-selection of peripheral blood stem cells were not found to be significantly associated with development of a secondary autoimmune disorder."

    Development of a secondary autoimmune disorder after hematopoietic stem cell transplantation for autoimmune diseases: role of conditioning regimen used

    http://www.bloodjournal.org/content/109/6/2643?ijkey=f1fa9dda39fd0787b81ac26cc6064d4b448a4ce3&keytype2=tf_ipsecsha

  • We have seen a few cases of vitiligo after #alemtuzumab in Cambridge.

    Now colleagues in Essen have written up three cases, making the point that "Secondary autoimmunity is not all about B cells". https://www.ncbi.nlm.nih.gov/pubmed/30404783?dopt=Abstract

    another example of keeping quiet?
    Maybe if the range of autoimmunities have been adequately reported we would be seeing this constant trickle.

    Today a case of Lamert Eaton…at type of Myaesthenia gravis (nerve muscle problem)

  • Vitiligo has been associated with Graves disease in general population and many patients have both (not sure if it is known which one is the initial trigger), but its interesting to note that alemtuzumab which causes graves disease (hiprrthyroidism) is also apparentely linked to vitiligo apearance.

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