Mortality due to invasive aspergillosis in graft -versus -host disease after experimental allogeneic bone marrow transplantation can be reduced by transfer of donor CD4+CD25+ regulatory T cells

Ref ID: 19600

Author:

B Echtenacher1*, K Doser2, M Edinger2, P Hoffmann2

Author address:

1Institute of Immunology, University of Regensburg, Regensburg, Germany
2Dept. of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany

Full conference title:

6th Advances Against Aspergillosis 2014

Abstract:

Purpose:
Graft-versus-host disease (GvHD) is a frequent and life-threatening complication after allogeneic
bone marrow transplantation (alloBMT). It is initiated by interaction of host antigen-presenting
cells with mature alloreactive donor T cells and leads to dysregulated pro-inflammatory cytokine
secretion and target organ destruction. Patients after alloBMT are severely immunocompromised
and thus particularly prone to opportunistic bacterial and fungal infections. We showed before that
co-transplantation of donor CD4+CD25+ Treg cells protects mice from lethal GvHD. We here tested
the impact of GVHD as well as of co-transplanted donor Treg cells on course and severity of an
opportunistic fungal infection after alloBMT.
Methods:
We employed a completely MHC-mismatched murine C57BL/6 into BALB/c alloBMT model.
Recipients with or without GVHD were infected with the clinically relevant pathogen Aspergillus
fumigatus on day 28 after BMT when the animals had recovered from irradiation-induced neutropenia
and symptoms of GvHD had developed. Part of the animals received donor CD4+CD25+ Treg cells
for GVHD prophylaxis.
Results:
After infection with Aspergillus fumigatus all animals with GVHD died within 10 d, whereas 60%
of the animals without GVHD survived for more than 35 d after infection. Survival of recipients
protected from GVHD after co-transplantation of donor CD4+CD25+ Treg cells was significantly
better than that of unprotected recipients with GVHD. Interestingly, initial clearance of the fungus
from the lung after i.t. infection, or from spleen, liver, lung, kidney and brain after i.v. infection,
was rapid and comparable in mice with and without GvHD. Later on, fungi (re)appeared in the
kidneys and fungal load increased significantly in moribund animals. Lymphocytes isolated from
spleen and liver of infected animals with GVHD and restimulated in vitro with germinating conidia
secreted significantly more pro-inflammatory TNF, IFN-γ and IL-6 than those from control mice.
Co-transplanted donor Treg cells did not interfere with early pathogen clearance, but normalized the
dysregulated cytokine secretion.
Conclusion:
Our data show that co-transplantation of donor CD4+CD25+ Treg cells protects mice not only form
lethal GvHD but also from infection-related co-mortality. Currently, we are investigating whether
the destruction of the kidneys by late outgrowth of residual fungal conidia is the main cause of
death or whether an uncontrolled anti-fungal immune response is primarily reponsible for the high
morbidity and mortality of opportunistic infections in GVHD.

Abstract Number: 125

Conference Year: 2014

Link to conference website: http://www.AAA2014.org

New link: NULL

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