the inflammatory process and immune reactions associated ...ucgatma/anat3048/lectures/revell...the...
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The inflammatory process The inflammatory process and immune reactions and immune reactions
associated with implant useassociated with implant useProfessor Peter A Revell
Implant Biology ResearchBiomaterials and Tissue Engineering Division
Eastman Dental InstituteLondon WC1X 8LD
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WHENEVER a foreign material, organisms or cells are introduced into the body, inflammatory and immunological reactions take place
Consider:-venesection and injectionssurgical implantsinfectionsblood transfusion organ transplantation
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WHENEVER a foreign material, organisms or cells are introduced into the body, inflammatory and immunological reactions take place
Consider:-venesection and injectionssurgical implantsinfectionsblood transfusion organ transplantation
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Use of implants in bone
Orthopaedics - joint replacement- fracture fixation- screws, nails, wires
Dentistry - dental implants
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When a joint is replaced, large pieces of foreign materials are placed in wounds created in bone by drilling, gouging and sawing
The healing process takes place in the continued presence of the foreign body which cannot, of course, be removed by any natural process
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Inflammation
• occurs when any foreign material is introduced into the body
• may be acute ( and transient) with resolution and healing
• may be chronic, when the noxious stimulus persists
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Resolution and healing
•inflammation resolves completely if damaging stimulus is removed OR
•healing with or without fibrous scarring
•may become chronic, when the noxious stimulus persists
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Chronic Inflammation
• typically shows the presence of macrophages and lymphocytes
• is accompanied by the development of an immune response
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Fibrous tissue and new bone formation
Lymphocytes, macrophages and multinucleate giant cells
(MNGC)
T & B cells, plasma cells
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Healing with fibrous tissue
IMPLANT
BONE
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Macrophages and multinucleate giant cells(MNGC) are found
-on biomaterial surfaces
-in relation to debris
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Development of osteolysis
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Aseptic loosening and osteolysis
Materialpropertiesdifference Micromovement
Wear debris &inflammation
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At implantation
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At implantation
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Professor Peter A RevellOsteoarticular ResearchDepartment of HistopathologyRoyal Free Campus Royal Free & University College Medical SchoolLONDON NW3 2PF Large particles in
giant cells
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There is gradual accumulationof particles deeper down betweenthe implant and the bone. This isaccompanied by an inflammatorycellular response which gives riseto bone loss - so called ‘osteolysis’
Particles can get down between the implant and bone carried by this fluid in continuity with the joint
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Osteolysis
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Macrophages & MNGCs
- ACTIVATED, expressing HLA-class II, cell surface epitopes, integrins (CD11a,b,c)(Revell & Jellie 1998; Curtis 2002)
CD11bαM / β2
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Human macrophage in tissue culture
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INTEGRIN Focal Adhesion Kinase
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Macrophages and foreign body multinucleate giant cells make cytokines, chemical mediators, which influence their own behaviour and that of other cells
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IL 1, IL 6, TNF are proinflammatorycytokines which perpetuate the inflammatory process. They have been shown in studies from various centresto be present in cells of the interface membrane and to be produced by macrophages on culture with particles.
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Activated macrophages & MNGCs
GMGM--CSFCSF
Bone
Implant
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Macrophages, giant cells and cytokines
TGFα, GM-CSF and M-CSF are responsible for promoting the formation of giant cells
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Pro-inflammatory
Osteoclastogenic
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Removal of bone by osteoclasts
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Lymphocytes are present
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Immune reactions
ave specificity ( antibody - antigen )
nvolve B lymphocytes and plasma cells which make antibodies OR
nvolve T lymphocytes which on stimulation produce chemical mediators
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An immune reaction is aimed at a particular target
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An immune reaction is aimed at a particular target
BUT
there may be collateral damage
HYPERSENSITIVITY REACTIONS
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Mast cells and antibodies
Antibodies
Antibodies
Cell mediated,T lymphocytes
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Clinical evidence forhypersensitivity reactions
in relation to implanted biomaterials
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Metal sensitivity in patients with orthopaedic implants Hallab, Merritt, Jacobs (2001) J Bone Jt Surg 83A 428-436
The prevalence of dermal sensitivity in patients with a joint replacement device, particularly those with a failed implant, is substantially higher than that in the general population
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THE ROLE OF LYMPHOCYTES
Passive role ? Bystanders ?
(Agins et al,1988; Lombardi et al, 1989;Santavirta et al, 1990,1991)
Active role ? Immune process ?
(Lalor & Revell, 1991;Weyand et al, 1998; Hercus & Revell, 2001; Bainbridge et al, 2001)
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(Lalor & Revell,1991; Revell et al,1997; Al Saffar & Revell,1999; Weyand et al,1998)
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6 to 16 per cent of cells
6 to 16 per cent of cells (Hercus, 2005)
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T lymphocytes having immune memory
CD 45 RO positive staining
(Revell & Al-Saffar, 1994)
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( Revell & Jellie, 1998 )
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Ki 67
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T H : T C / S = 7.2 : 1
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Determine which sub-type of T helper lymphocyte
is involved in theimmunological process
Th 1 cells Th 2 cellsCell mediated immunity Humoural immunityMacrophages & natural B lymphocytes &
killer (NK) cells plasma cells
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Helper T cell polarisation
Th1 > Th2 (Weyand et al ,1998; Hercus & Revell, 2001; Hercus, Saeed & Revell, 2002;Hercus, 2005)
No Th1 predominance (Arora et al, 2003)
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Helper T cell polarisation
Multiplex PCR (Hercus)
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Helper T cell polarisation
Cytokine profile
Th1 cell IL-2, IL-12 & IFN-γ
Th2 cell IL-4, IL-5 & IL-10
Th1 > Th2 Contact sensitisation process
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T lymphocytes in the interface tissues in known nickel sensitivity
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CD45Ro positive lymphocytes
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Bainbridge, Revell & Al-Saffar (2001) J Biomed Mater Res 54, 328
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Antigen presenting cells
Bainbridge, Revell & Al-Saffar (2001) J Biomed Mater Res 54, 328
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Macrophages and lymphocytes
Macrophages and lymphocytes
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P selectin
E selectin
E-selectin mediates T cell adhesion to endothelial cells and migration in skin contact hypersensitivity (Norris et al, 1991; de Vries et al, 1997)
Other adhesion molecules are also present (Revell et al, 1997; McFarlane & Revell, 2004)
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Functional studies
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Western blot of IL15 protein prior to deglycosylation: A
rHuIL15, B-E interface samples
Western blot of IL15 protein after
degycosylation: A rHuIL15, B-D interface samples
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Macrophages and the IL15 receptor
Lymphocytes and the IL2 receptor
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Ki 67
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Macrophages and lymphocytes
CD40 Ro
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Interleukin 15 is able to sustain the proliferation and survival
of T lymphocytes
In coculture experiments T lymphocytes are sustained
by U937 macrophagesphagocytosing particles
(Saeed, Damien and Revell, 2002a)
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Submicron sized particles can be isolated from perimplant tissues and characterised
Phagocytosis of these particles activates macrophages which produce cytokines
Some of these are “pro-inflammatory”,others promote giant cell formation
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The inflammatory response to the persistenceof these particles gives rise to bone loss
and implant loosening
Activated lymphocytes are present in large numbers in some cases
Immune sensitisation may be present in response to some metals
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Evidence of sensitisation is provided by:-
•activated and proliferating T lymphocytes•T cells sustained by IL15•T helper cell predominance and T H1 > T H2•T memory cells•presence of P- and E-selectins on vessels•evidence for antigen presentation
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