[CIS-PAGID] Transplantation for APECED ?. .
Nelson, Robert P Jr
ronelson at iupui.edu
Tue Aug 9 12:18:56 EDT 2011
I have a patient with thymoma and recurrent moderately severe candidiasis. Would you have a resource for measurement of Th-17 aabs and if so, who could I talk to about sending a sample? Thank-you for this consideration.
Bob
________________________________________
From: pagid-bounces at list.clinimmsoc.org [pagid-bounces at list.clinimmsoc.org] on behalf of Desa Lilic [desa.lilic at newcastle.ac.uk]
Sent: Thursday, July 14, 2011 5:38 AM
To: 'pagid at list.clinimmsoc.org'
Cc: 'Mario.Abinun at newcastle.ac.uk'
Subject: [CIS-PAGID] Transplantation for APECED ?. .
Our understanding of APECED as a uniquely thymic defect may have been biased by mouse models that only partially reflect human disease. Recent data on anti-cytokine autoantibodies to IFN type 1 (PLoS 2006) and Th-17 (JEM 2010) points to more complex mechanisms of autoimmunity than just defective central tolerance due to lack of ectopic expression of tissue specific antigens in AIRE-mutated thymi (thymic secretion and presentation of cytokines has been documented but does not prevent autoimmunity - see PLoS 2006). Also, a role for AIRE in peripheral antigen presenting cells is well recognised but poorly understood. Importantly, we and others have reported T regulatory cell defects in APECED patients that may have a crucial role in the autoimmune pathology of APECED patients (JACI 2005, J Autoimmunity 2010, Scan J Immunol 2011)
Based on the above and the fact that this young lady suffers with what seems to be aplastic anemia due to bone marrow insufficiency, I would not dismiss the possibility that allogeneic HCT could be beneficial. However, before focusing on HCT, it may be worth considering a trial of alemtuzumab (Campath) - based on personal experience of my colleague (and husband...) Dr Mario Abinun, Paediatric Immunologist, who observed a good clinical and histological response in a young APECED lad with severe autoimmune hepatitis.
Lastly, as regards diagnostic anti-cytokine antibodies in APECED pts (btw - IFN type 1 are more sensitive but as specific as Th-17 aabs) we can do this in the UK so pls let me know if you need further details. However, diagnostic IL-17 production (for other CMC subgroups) is not routinely available.
Desa Lilic MD MSc PhD FRCPath
Consultant & Hon Clin Sen Lecturer in Immunology
Newcastle University
>-----Original Message-----
>From: pagid-bounces at list.clinimmsoc.org [mailto:pagid-
>bounces at list.clinimmsoc.org] On Behalf Of Conley, Mary Ellen
>Sent: 13 July 2011 19:31
>To: 'pagid at list.clinimmsoc.org'
>Subject: Re: [CIS-PAGID] Transplantation for APECED ?. .
>
>Maybe we can take a different point of view. Some patients with
>DiGeorge Syndrome have been treated with allogeneic transplants (Blood.
>2010 Sep 30;116(13):2229-36) with some patients doing moderately well.
>This suggests that the mature T cells in the graft may provide
>sufficient protection from infection. If there were a perfect matched
>sib or MUD for your patient, you might be able to use thymectomy and an
>ablative prepartive regimen. Yes, I know, its a radical approach. But
>it might work.
>Mary Ellen
>
>
>
>
>
>
>Mary Ellen Conley, MD
>Department of Immunology/ Mail Stop 351
>St. Jude Children's Research Hospital
>262 Danny Thomas Place
>Memphis, TN 38105-3678
>FAX 901-595-3977
>TEL 901-595-2576
>
>
>-----Original Message-----
>From: pagid-bounces at list.clinimmsoc.org [mailto:pagid-
>bounces at list.clinimmsoc.org] On Behalf Of Notarangelo, Luigi
>Sent: Wednesday, July 13, 2011 1:09 PM
>To: pagid at list.clinimmsoc.org
>Subject: Re: [CIS-PAGID] Transplantation for APECED ?. .
>
>Dear Elie:
>
>As you pointed out, HCT should not work for APECED because Aire is
>mostly expressed by mTECs. However, it is interesting to know that
>conflicting results have been obtained with HCT in aire KO mice, with
>two groups reporting either complete failure or successful correction of
>autoimmunity. I do not think that anybody has looked carefully into
>this, and I wonder whether: a) "resetting" of the immune system could be
>explanation for success 9at least in some cases); or b) aire expression
>by donor-derived myeloid cells might partially compensate for the
>defect. In any case, I think there is insufficient evidence (if any)
>that HCT would work, unless you bet specifically on resetting of the
>immune system (but even so, attempts with autologous HCT for
>autoimmunity are less popular now than they were until few years ago, I
>guess?)
>
>Gigi
>
>
>Luigi D. Notarangelo, M.D.
>Jeffrey Modell Chair of Pediatric Immunology Research in Boston
>Director, Research and Molecular Diagnosis Program on Primary
>Immunodeficiencies Division of Immunology, Children's Hospital Professor
>of Pediatrics and Pathology, Harvard Medical School Karp Building, 9th
>floor, Rm 09210
>1 Blackfan Circle
>Boston, MA 02115
>USA
>
>(tel) (617)-919-2276
>(fax) (617)-730-0709
>
>
>Secretary: Luisa Raleza
>email: luisa.raleza at childrens.harvard.edu
>
>
>
>
>On 7/13/11 12:04 PM, "Elie Haddad" <elie.haddad at umontreal.ca> wrote:
>
>Dear all,
>I follow a 22 years old girl with APECED (proven AIRE mutation) with
>very severe autoimmunity.
>The only treatment that was considered efficient was Rituximab for many
>years (since 2005) and she was treated by one injection every 6 months.
>I informed the patient about the risks of repeating Rituximab but she
>said that her endocrinologic autoimmunity was very uncomfortable and the
>only treatment that worked was Rituximab and she did not want to stop.
>18 months ago, she presented with extensive pulmonary embolism related
>with deep venous thrombosis (we did not understand why she did this)
>that could be efficiently treated. During the hospitalization, we
>noticed a very severe anemia that did not resolve and that was
>eventually considered as autoimmune central anemia. Indeed, the anemia
>was central, Epo was normal, there was no anti-Epo antibodies, and
>marrow specimen showed plenty of T cells infiltrating the marrow and
>surrounding reticulocytes (I could not see the slides, this is what said
>the haematologist). To treat this autoimmune central anemia, we stopped
>Rituximab and tried ATG + FK506 and then MMF in accordance with
>haematologist advise. This treatment was unsuccessful and she is
>presently transfused with red cells every 3 weeks with ferritin
>dangerously growing up (even if somewhat stabilized by oral iron
>chelation)... We are therefore facing a very severe autoimmune central
>anemia that is resistant to Rituximab (that has been restarted recently
>to control her endocrinologic autoimmunity), MMF, anti-Calcineurine,
>ATG. She is under sub-cu IG for immunoglobulin replacement because of
>repeated rituximab. Given the T cell infiltrate in marrow (that is not a
>leukemic infiltrate), we consider that we are facing a T cell
>autoimmunity and we don't feel that plasmapheresis could work.
>The question is regarding bone marrow transplantation. I know it may be
>a strange idea but our haematologist colleagues propose to perform an
>allogenic HSCT. I would like to have your opinion. Given that AIRE
>deficiency is a thymic disorder, allogenic HSCT should not work. The
>only way it could work would be that thymus function in older patients
>is not perfect and that the new immune system may not be miseducated.
>However, if this theory works, then an autologous HSCT after < radical >
>immunosuppression to "reset" the immune system should work also and
>would be less dangerous than an allo-HSCT.
>What do you think ? Allo ? Auto ? Has anyone already done an HSCT for
>APECED ? HSCT (auto or allo) doesn't make any sense ? Other proposition
>to treat this autoimmunity?
>Thank you for your feedback.
>Elie
>
>PS: sorry for the long text (it's a complicated story), and sorry for
>the possible English mistakes from a "French" Canadian.
>
>
>Elie Haddad, MD, PhD;
>Professor of Pediatrics, University of Montreal, Head, Pediatric
>Immunology and Rheumatology Division, CHU Sainte-Justine, 3175 Cote
>Sainte-Catherine Montreal, QC, H3T 1C5, Canada
>Ph: 1 514 345 4713
>fax: 1 514 345 4897
>e-mail: elie.haddad at umontreal.ca
>
>
>
>
>
>
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