[CIS-PAGID] Transplantation for APECED ?. .

[Nelson, Robert P Jr]

Desa-thank-you.  Bob

Robert P. Nelson Jr., MD
Professor of Medicine and Pediatrics
Divisions of Hematology/Oncology
535 Barnhill Dr. Ste 473
Indianapolis, IN  46202
Telephone: 317-948-1186
E-mail: ronelson at iupui.edu
pager:  317-312-1773


-----Original Message-----
From: pagid-bounces at list.clinimmsoc.org [mailto:pagid-bounces at list.clinimmsoc.org] On Behalf Of Desa Lilic
Sent: Thursday, July 14, 2011 11:11 AM
To: 'pagid at list.clinimmsoc.org'
Subject: Re: [CIS-PAGID] Transplantation for APECED ?. .

Hi Bob
I attach our anti-IL-17 paper (collaboration with Jean-Laurent Casanova at Rockefellar) where one of the 2 first authors is Rainer Doffinger in Cambridge who does anti-IFN as well as anti-Th-17 autoantibody evaluation (it might be best to communicate with him directly about what your needs are - rd270 at cam.ac.uk). J-L's group also did this (it's closer to home for you) but I don't think they offer them routinely.

I also attach our previous paper on the diaganostic value of anti-IFN aabs (in collaboration with Nick Willcox - Oxford who was the first to describe them - PLoS 2006) but they do not offer them routinely.

Hope this helps. All best
desa


>-----Original Message-----

>From: pagid-bounces at list.clinimmsoc.org [mailto:pagid- 

>bounces at list.clinimmsoc.org] On Behalf Of Nelson, Robert P Jr

>Sent: 14 July 2011 15:43

>To: 'pagid at list.clinimmsoc.org'

>Subject: Re: [CIS-PAGID] Transplantation for APECED ?. .

>

>Dr. Lilic,

>

>I would like further details regarding the anti-type I interferon and

>anti-IL-17 antibody testing.  Thanks.

>

>Bob

>

>Robert P. Nelson Jr., MD

>Professor of Medicine and Pediatrics

>Divisions of Hematology/Oncology

>535 Barnhill Dr. Ste 473

>Indianapolis, IN  46202

>Telephone: 317-948-1186

>E-mail: ronelson at iupui.edu

>pager:  317-312-1773

>

>-----Original Message-----

>From: pagid-bounces at list.clinimmsoc.org [mailto:pagid- 

>bounces at list.clinimmsoc.org] On Behalf Of Desa Lilic

>Sent: Thursday, July 14, 2011 5:39 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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