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Title: Evaluation of the role of complement in developmnent of graft versus host disease following bone marrow transplantation in a murine model

Abstract:

Graft-versus-host disease (GvHD) is the major complication of allogeneic hematopoietic stem cell transplantation. Standard immunosuppressive regimen used for its prevention and treatment is only partially effective and it is associated with considerable side effects. This justifies further research focused on pathophysiology of GvHD and aiming at development of new strategies to control the disease. Recent research has shown that the complement system which is the central element of innate immunity also regulates adoptive immune response and tissue regeneration. Therefore, participation of complement in development of GvHD seems probable. This hypothesis is supported by involvement of complement in organ graft rejection. Activation of complement has been detected during GvHD in animal models and it has been suggested that it may participate in tissue injury observed in the course of the disease. However, there is lack of published data allowing to estimate the significance of complement for pathophysiology of GvHD. The aim of the study was to evaluate the role of complement in pathogenesis of GvHD employing C3 complement factor knock-out animals. Within 14 experiments 119 C57BL/6 C3 knock-out (C3-/-) mice and 104 C57BL/6 wild-type (C3+/+) animals were transplanted with allogeneic bone marrow cells and splenocytes isolated from MHC mismatched C3H.He mice. Sex mismatched transplants were performed to monitor chimerism of transplanted mice by means of sry gene detection by PCR and real time PCR. Furthermore, 60 C57BL/6 syngeneic transplantations and 8 C3H.He syngeneic transplantations were performed to provide control groups (without GvHD). All the transplantations were preceded by total body irradiation. Following transplantation, mice were weighted and physically examined by looking for changes in skin and posture. Peripheral blood morphology assessment and flow cytometry analysis of peripheral blood lymphocytes were performed for some animals on days +17, +31 and +45. Additionally, detection of TREC-positive cells was performed on day +45. Histological examination of liver, skin, colon and spleen was performed on day +8 and +16. In mice transplanted with allogeneic cells evident symptoms of GvHD were observed in physical examination (weight loss, skin desquamation, hunching), in analysis of peripherial blood lymphocytes (lymphopenia, increased expression of CD69 activation antigen on CD3+CD4+ and CD3+CD8+ cells, deficiency of TREC-positive cells) and in histological picture of examined organs. The most important difference between C3-/- and C3+/+ allogeneic graft recipient populations was significantly better survival of wild type animals (HR 1,6; p=0,0273). Presence of valid complement system was also associated with beneficial effect on weight of transplanted animals. A characteristic pattern of body loss consisting of a fall to approximately 86% of initial body weight on day +7 followed by return to the initial weight on days +14 to +17 and another decrease leading either to the death of the animal or to a long time plateau was observed in all allotransplanted mice. However, the average relative weight (percentage of the initial body mass) of C3+/+ animals was constantly higher. Particularly, more dynamic increase of body weight of wild-type animals was observed on days +10 to +17 (average relative body weight of C3+/+ mice was higher by 2,63%; p=0,0001). Interestingly, the body weight on day +10 strongly correlated with overall survival (p=0,002). Skin changes tended to be less severe in wild type animals but statistically significant effect was detected only in the case of the skin of paws (p=0,0007). Analysis of peripheral blood revealed higher WBC (by 3,31 x 103/l; p=0,0213), higher number of CD3+CD4+ (by 1,31 times; p=0,0293) and higher CD4/CD8 ratio (1,42 times; p=0,0079) in C3-/-. Skin changes observed in histopathological examination on day +16 were more intense in wild type allogeneic graft recipient mice. ; Observed differences in course of GvHD in C3+/+ and C3-/- mice, and foremost a better survival of wild type animals suggest that complement may have a beneficial role in ameliorating consequences of GVHD in mice.

Level of degree:

2 - studia doktoranckie

Degree discipline:

immunologia ; hematologia ; transplantologia

Degree grantor:

Wydział Lekarski

Promoter:

Marcin Majka

Date issued:

2007

Format:

application/pdf

Identifier:

oai:dl.cm-uj.krakow.pl:1001

Call number:

ZB-107538

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Access rights:

tylko w bibliotece

Location of original object:

Biblioteka Medyczna Uniwersytetu Jagiellońskiego - Collegium Medicum

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Last modified:

Feb 12, 2020

In our library since:

Nov 21, 2012

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4

All available object's versions:

http://dl.cm-uj.krakow.pl:8080/publication/1001

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ZB-107538 Feb 12, 2020
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