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 Updated on: Jan 9 2014

Immune system and microenvironment

Immune system and microenvironment: immunophenotype, adhesion molecules, cytokines, stroma, immune response, angiogenesis, bone lesion

 

Subject
Typically myelomatous plasma cells are terminally differentiated, low-proliferative B-cells that display a survival advantage associated with resistance to apoptosis after cytotoxic therapies. Despite the fact that the existence of underlying genetic abnormalities is considered a pre-requisite for the malignant transformation of myelomatous plasma cells, increasing evidence supports the idea that both the host immune system and the bone marrow microenvironment play a crucial role in determining the behaviour of the disease.


Present Status
The existence of abnormalities in the immune system from patients with monoclonal gammopathies, that involve both its cellular and soluble compartments, has long been reported.


These include:

1) an abnormal distribution of peripheral blood lymphocytes with low CD4 counts and increased numbers of functionally altered killer cells,

2) abnormal expression of apoptotic receptors (e.g. fas) and intracellular proteins (e.g. bcl2) on T-cells,

3) decreased expression of killer-receptors on CD8+ lymphocytes,

4) partial loss of the diversity of the TCR repertoire,

5) presence of a monoclonal component associated to polyclonal hypogammaglobulinemia,

6) increased serum levels of inflammatory cytokines (e.g. IL6, Il1b) and other proteins which may interfere and modulate immune responses (e.g. HLA-Ia, B2-microglobulin, CD16).

Despite the fact that many of these latter soluble factors and cytokines are produced by the BM microenvironment and/or by the clonal plasma cells and that they have been shown to play an active role in priming, activating, inhibiting and or just modulating immune responses, no clear link has been established so far, between the events occurring in the bone marrow microenvironment containing most of the neoplastic plasma cells and the immunological compartments.

 

Preview of Programme Proposed
To analyse the specific role of the immune system from patients with MM on modulating tumour cell growth, apoptosis and drug resistance. Determine the influence of the bone marrow microenvironment on the correct functionality of the immune system by;
 

  • determinating the genetic expression profiles of inflammatory cells from peripheral blood and bone marrow samples and its potential influence on BM microenvironment and the clonal plasma cells
  • exploring the effects of stromal cell derived factors such as IL6, and SDF1 on the functionality of inflammatory cells, CD4+ lymphocytes and cytotoxic cells from patients with monoclonal gammopathies.
  • analysing the potential effects of beta-2 microglobulin, HLA-Ia molecules and serum IgG and IgA monoclonal components on modulating normal immune responses in patients with monoclonal gammopathies.
  • evaluate the potential clinical implications of the above findings.

Deliverables and Cooperations
The following deliverables are expected from this section;

  • a catalogue of the genetic expression profiles of inflammatory cells from patients with multiple myeloma (MM), under different environmental/disease states. Previewed format for this catalogue includes both publications in scientific journals and a database
  • a network map dissecting the interactions occurring between the immune system and both clonal plasma cells and bone marrow stromal cells, in MM patients. This will be made available to the scientific community through and an electronic interactive file
  • a chart describing the effects of the immune response and the elements of the immune system on the most relevant functions of clonal plasma cells (proliferation, apoptosis and drug resistance) pinpointing the potential pathways that could be targeted by new therapies. The format of this deliverables includes both scientific publications and educational software-based material
  • identification of new prognostic factors of the disease related to the plasma cells (PC) microenvironment, is expected. Integration of these with other PC-related prognostic factors is expected to provide the basis for a new classification for prognostic-stratification of MM with a direct impact on the treatment-decision making process
  • software-based interactive/Educational material for a better and easer understanding and an external educational program of the role of the immune system in MM
  • standardized protocols for the study of different aspects of the immune system and clonal PC that could be applied routinely.


This project will cooperate with other areas of the network including area;

 

B.4.2.1 (identification of new PC proteins that might interact with the microenvironment),
B.4.2.3 (mechanisms of PC proliferation and death that could be influences by the immune system),
B.4.2.5 (use of developed animal models),

B.4.2.7 (integrated information on new prognostic factors associated with the immune system),

B.4.2.10 (Identification of new potential therapy targets related to the interactions of the immune system with clonal PC), 
B.4.2.11 (provide new standard operating procedures for the assessment of specific immune system related parameters that could be easily used in the context of clinical trials).

 

Beyond 18 months the primary goal is to develop a strategy to define, and to initiate a coordinated effort to perform a common research program between the participants in this area

Secr. Hans E. Johnsen | Depart. of Haematology | Aalborg University Hospital | Sdr. Skovvej 15 | DK-9000 Aalborg | Denmark | T:+45 9766 3871 | F:+45 9766 6369