Chapter 29 dendritic cells

Chapter 29 dendritic cells

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  DENDRITIC CELLS By DR.BHAVIN VADODARIYA DNBSurgical Oncology Resident, Apollo CBCC Cancer Care, Ahmedabad
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   Dendritic cells(DCs), named for their probing, ‘tree- like’ or dendritic shapes, are responsible for the initiation of adaptive immune responses and hence function as the ‘sentinels’ of the immune system. Paul Langerhans first described DCs in human skin in 1868 but thought they were cutaneous nerve cells. DCs are bone marrow (BM)-derived leukocytes and are the most potent type of antigen-presenting cells. They can also be propagated in vitro from BM and blood using various combinations of growth factors, such as granulocyte macrophage-colony stimulating factor (GM-CSF) and Flt3 ligand.
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   DCs arespecialised to capture and process antigens, converting proteins to peptides that are presented on major histocompatibility complex (MHC) molecules recognised by T cells. DCs are heterogeneous, e.g. myeloid and plasmacytoid DCs; although all DCs are capable of antigen uptake, processing and presentation to naive T cells, the DC subtypes have distinct markers and differ in location, migratory pathways, detailed immunological function and dependence on infections or inflammatory stimuli for their generation. During the development of an adaptive immune response, the phenotype and function of DCs play an extremely important role in initiating tolerance, memory, and polarised T-helper 1 (Th1), Th2 and Th17 differentiation.
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   Since DCshave numerous cytoplasmic processes, they have a high surface area permitting intimate contact with a large number of surrounding cells, e.g. T cells, natural killer cells, neutrophils, epithelial cells etc. For instance, experimentally, only one mature DC (mDC) is required to stimulate 100– 3000 T cells. DC precursors migrate from the BM through the blood stream to almost every non- lymphoid tissue, where they reside in an immature state (iDC), continuously sampling their environment by endocytosis, macropinocytosis, and phagocytosis.
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   They canextend their processes through the tight junctions of epithelia to increase capture of antigens even when there is no overt infection/inflammation. During pathogen invasion, resident iDCs detect intruders via pattern recognition receptor (e.g. TLRs) capture antigens and quickly leave the tissue. They crawl through the cells, cross the endothelium of lymphatic vessels and migrate to the draining lymph nodes (LN) in response to a number of chemokines such as CCL19 and CCL21.
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   During theirmigration from the peripheral tissues, DCs undergo phenotypical and functional maturation. Most remarkably, they stop capturing antigens while up-regulating the expression of co- stimulatory molecules such as CD80 and CD86 and the chemokine receptor CCR7, and secrete pro-inflammatory cytokines such as TNF-α and IL- 12. After reaching the subcapsular sinus of the LN, DCs move to T-cell zones. Here, the interdigitating DCs are actively involved in the presentation of antigens to T cells.
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  INTRODUCTION  Dendritic cellsconsidered the pacemakers of the immune system, were originally identified by Steinman and his colleagues in the early seventies.  They are crucial to the presentation of peptides and proteins to B and T lymphocytes and are the key antigen presenting cells.  They are critical for the induction of T cell responses resulting in cell mediated immunity.
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   t isthe T cell receptors on the T lymphocytes which recognize fragments of antigens bound to molecules of the major histocompatibility complex (MHC) on the surfaces of dendritic cells (DC).  The peptide binding proteins, which are of types I and II, interact with and stimulate cytotoxic T lymphocytes (CTLs) and T helper cells.  The antigens from a cancer cell on entry into the APC, are processed, spliced into peptides and then re-expressed on the cell surface linked to MHC proteins.
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   This resultsin generation of CTLs which recognized and destroy only cancer cells which express the antigen. The T helper cells which when activated in turn have profound immunoregulatory effects.  Therefore, DC play a key role in host defenses and a crucial role in anti-cancer immune responses.
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  WHY DENDRITIC CELLS? Antigen Presenting cell  There capacity to activate naïve T cells  There ability to migrate through tissue and act on tumors
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   DC immunotherapy Exploiting the immune-regulatory capacities of DCs holds great promise for the treatment of cancer, autoimmune diseases and the prevention of transplant rejection. Manipulation of DCs could turn them into the most effective adjuvant to enhance the host's immune defences. In the case of cancer, tumours have been shown to suppress DCs by secreting anti-inflammatory cytokines such as IL-10, and therefore conditioning the local DCs to form suppressive T cells.
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   In orderto subvert these mechanisms, DCs could be generated ex vivo, loaded with tumor antigens, and re-injected to boost the host’s immunity against the tumour cells. DC vaccines generated in this way are generally safe with minimal side effects, and have proven to be feasible, and effective in some patients. Other strategies exploiting DCs in various disorders have also been described and are being investigated in clinical trials.
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   These maturedendritic cells are re-infused to the same patient after eight days of culture for generating specific anti-cancer immunity.  After infusion, these dendritic cells along with specific cytokines are carried to various lymph nodes and station themselves in these lymph nodes.  They start their physiological action on naïve T cells. Upon physiological contact with dendrites of DC, T cells become committed in the vicinity of dendritic cells. Each dendritic cell has the potential to mature to about 3000-5000 T cells/hour.  Dendritic cell survives on an average of 3 weeks to months, and during this period it is able to selectively transform trillions of T cells.  The robust anticancer immunology doesn’t allow new malignant cells to grow and effectively stops or delays tumor progression.  Dendritic cells leading to IL-12 and TNF-alpha generation also generate humoral immunology which results in reducing cachexia.