[CIS-PAGID] Transplantation for APECED ?

[Jack Bleesing]

If I would be running out of treatment options, I would go with the
"resetting" clause and at least try high-dose immunosuppressive
resetting followed by autologous rescue. Immune reconstitution in the
presence of abundant autoantigens (this time around) may alter the
central and peripheral selection/deletion process (receptor editing?) in
a way that might allow this to work.
 
Furthermore, I guess patients aren't always KO mice and perhaps some
AIRE is better than none.
 
j
 
 
 
---------------------------------------------------------------------------
Jack J.H. Bleesing, M.D., Ph.D.
Associate Professor of Pediatrics
Cincinnati Children's Hospital Medical Center
Division of Bone Marrow Transplantation & Immune Deficiency
3333 Burnet Avenue, MLC 7015
Cincinnati, OH 45229
513-636-4266 (phone)
513-636-3549 (fax)
Jack.Bleesing at CCHMC.org 
http://www.cincinnatichildrens.org/immunodeficiencies/ 


>>> "Notarangelo, Luigi" <Luigi.Notarangelo at childrens.harvard.edu>

7/13/2011 2:08 PM >>>
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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