[CIS-PAGID] Transplantation for APECED ?. .

[Desa Lilic]

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

>

>

>

>

>

>

>Email Disclaimer:  www.stjude.org/emaildisclaimer