Immunity Overview Blood 2018 Nurses Education Day · 2018. 10. 23. · T-cells (cell mediated immunity) Natural killer cells The Amgen slide identifies the NK cell as a myeloid differentiating

Immunity Overview

Blood 2018Nurses Education Day

Ron Middleton

Haematology Care Coordinator /

Clinical Nurse Consultant

Cancer Care Services

Toowoomba Hospital

Disclosures

• Amgen Sponsorship for HSANZ / CNSA Myeloma Education Day, April

2018

Accommodation

• Roche Sponsorship for Roche: Follicular Lymphoma Nurses &

Pharmacists, July 2018

Flights & accommodation

• Photographs

Objectives

• Identify the complexity of immunity

• Overview of immunity

• Identify specific functions on immunity

• Impacts of haematology diagnosis & treatments on the immune system

• Factors to identify the at risk patients

• Identify resources for nurses to access

The Observable Universe - Immense

The Universe (Time & Matter)• Ordinary matter makes up only 4.9% of the observable

universe Atoms / stars / galaxies

400 billion to 2 trillion galaxies

300 sextillion stars (3 x 1023)

• More stars than grains of sand on earth

• Hubble telescope has helped identify 125 billion galaxies

• Milky Way is part of a Local Group galaxy – Laniakea Supercluster Milky Way – 150,000 to 200,000 light years wide

Laniakea Supercluster – 10 million light years

Our small perspective – Milky Way

Yosemite NP, USA Melany, QLD

The Immune System – Universally Immense

• Our immune system can seem just as complex as the universe we live in

• Body 100 trillion cells

200 different cell types

• Nervous system Brain has 100 billion neurons

10-50 trillion neuroglia

Spinal cord has 100 million neurons

1 trillion synapses (more stars than our galaxy) in the brain

• Smell Humans can identify 10,000 different odours / 10-100 million receptors in our nose

• Blood Bone marrow makes 2-3 million cells per second to maintain our blood volume / functioning cells

Each red blood cell contains 280 million haemoglobin molecules

Each megakaryocyte splinters into 2,000 – 3,000 platelets

Immunological Effects

Congenital disorders

cell line specific

coagulation

autosomal dominant

autosomal recessive

sex linked – X-chromosome disorders

Multi-factor

nutritional deficiency

B12 / iron deficiency

environmental / chemical

other disease processes

unknown causes

Immunological Effects

Immunological disorders

Acquired Immune Deficiency Syndrome (AIDS)

Agammaglobulinemia

Neoplastic disorders

Leukaemia

Lymphoma

Myeloma

Myeloproliferative disorders

Lymphoproliferative disorders

Myelodysplastic Syndrome

Solid tumour with bone marrow infiltration

Immune System

• The body is constantly adapting and adjusting to maintain stable status - homeostasis

• Our immune system helps to maintain this balance.

• Multiple other systems also help to maintain this balance

• The basics is to understand haematopoiesis The blood

The cells

Their function

PluripotentStem Cell

CFU-Blast

CFU-GEMM Lymphoid Stem Cell Natural Killer

Precursor

Stem Cell

Self-Replication/

Differentiation

Haematopoiesis • All blood cells commence with the pluripotent stem cell

• If damage to these stem cells, then failure of the all blood cells to develop – bone marrow failure

• The pluripotent cells divide – 2 cells form 1 cell will further develop & differentiate

The other returns to being a stem cell

In theory we have the same number of stem cells during life

Approximately 400 stem cells in our circulation at one time

2-5 million needed for bone marrow / stem cell transplantation

• The cells differentiate into myeloid or lymphoid cells

There is multiple feed back mechanisms in the body to stimulate differentiation

Different cytokines involved with proliferation and differentiation

PluripotentPluripotentStem CellStem Cell

CFU-BlastCFU-Blast

CFU-GEMMCFU-GEMM

BFU-EBFU-E

CFU-ECFU-E

ReticulocyteReticulocyte

RedRed

Blood CellBlood Cell

CFU-MegCFU-Meg

Megakaryocy teMegakaryocy te

Plate letsPlate lets

CFU-GMCFU-GM

CFU-MCFU-M

MonocyteMonocyte

MacrophageMacrophage

CFU-GCFU-G

NeutrophilNeutrophil

CFU-CFU-EoEo CFU-CFU-BaBa

Eos inophilEos inophil

Bas ophilBas ophil

Natural K illerNatural K iller

PrecursorPrecursor


CellCell

ProplateletsProplatelets

CFU-MastCFU-Mast

Tissue Mas t CellTissue Mas t Cell

Myeloid LineageMyeloid Lineage

Myeloid Lineage

• Myeloid progenitor cells commit to myeloid differentiation and proliferation (colony forming units - CFU)

• Once designated to a specific CFU for a specific lineage

Erythrocyte (CFU-E)

Megakaryocyte (CFU-Meg)

Granulocyte-macrophage (CFU-GM)

Granulocytes

Monocytes

• Differentiation and proliferation regulated by haemopoietic growth factors / Interleukin's

White Blood Cells

• Granular leukocytes

Neutrophil

Eosinophil

Basophil

• Agranular leukocytes

Lymphocyte

Monocyte

Neutrophils• Action of phagocytosis (engulf bacteria)

• Can migrate out of the blood stream to areas of inflammation / infection

• Emigration – white cells leave through blood vessel walls

• Adhesion molecules – stick to blood vessel endothelium in response to nearby injury and assist with neutrophil movement through blood vessels

• Chemotaxis – chemical stimulus to attract neutrophils (released from microbes and inflamed tissue) Chemotaxis also enhances phagocytic action

• Lysozyme & strong oxidants contained within neutrophils are activated to destroy the pathogen

• Defensins, proteins with the neutrophil merge with phagosomes containing microbes to ‘spear’ holes in the microbe membrane

Neutrophils

• Neutrophil clearance of infectious organisms is critical to the immune response (need neutrophil numbers and function)

• Circulate in the blood in a quiescent ‘surveillance’ state and react weakly to stimuli in normal body state

• Priming of neutrophils May not immediately activate an effector response

May allow a later exaggerated response upon stimulation

Main antagonists Chemotactic inflammatory mediators

Serum immunoglobulins

Complement opsonins and inflammatory cytokines

Eosinophils

• Phagocytic action

• Leave capillaries and enter tissue fluid

• Release histamine & enzymes involved in inflammatory response

• Phagocytic against antigen-antibody complexes

• Active against fungal & parasitic infections

• Important part in pathogenesis of malignant disease processes

• Eosinophilic granules contain numerous proteins for mentioned functions

Basophils

• Can exit capillaries and enter body tissues

• Have granules

Contain heparin / histamine / serotonin

• Intensify inflammatory actions and hypersensitivity reactions

Receptors that bind with Fc portion of IgE antibodies

• Similar action to mast cells

found in connective tissues of skin, mucous membranes of respiratory and GI tract

Monocytes

• Ability of phagocytosis

• Slow to migrate that neutrophils

• Arrive in large numbers and have very potent activity

• Also progress into macrophages

• Macrophages are able to live in tissues of the liver / GI tract for early defence recognition

PluripotentPluripotentStem CellStem Cell

CFU-BlastCFU-Blast

Lymphoid Ste m CellLymphoid Ste m Cell

Lymphoid Lymphoid

LineageLineage

Pre-B CellPre-B Cell Pre-T CellPre-T Cell

B LymphocyteB Lymphocyte

T LymphocyteT Lymphocyte

Plasma CellPlasma Cell

Lymphocytes

• Major component of the immune system

• Originate in the bone marrow from the lymphoid stem cell. Differentiate into

B-cells (humoral immunity)

T-cells (cell mediated immunity)

Natural killer cells

The Amgen slide identifies the NK cell as a myeloid differentiating

Shows changes in our understanding cell development & differentiation

• Lymphocytes continue to migrate from lymphoid tissue – lymph fluid and blood

• Only a small number circulate in the blood at one time

T-lymphocytes

• Develop from pluripotent stem cell

• Migrate and mature in the thymus

• 95% die in the thymus

• The surviving T-cells develop as CD4+ or CD8+ cells

• Live in the lymphoid system as naïve precursors

• Can live for many years

• Help identify self / non - self body cell

• Function of T-cells Provide signals to help induce T-cells & B-cells to proliferate &

differentiate Specifically deleting viral infected cells or foreign cells Activate macrophages to enhance cellular cytotoxicity Regulation of established immune responses

B-Lymphocytes

• Originate from pluripotent stem cell

• ‘B’ for bursa of Fabricus – where B-cells develop in birds

• Naïve B-cells enter the lymphoid circulation

• When triggered by peripheral antigen – some B-cells return to the bone marrow as long lived plasma cells

• B-lymphocytes are precursors of antibody producing cells.

• Each B-cell produces and expresses on it’s surface; immunoglobulin with distinct specificity for the antigen

NK cells

• Thought to develop within the bone marrow

• Can kill cells that don’t express major histocompatibility complex (MHC) Class1

• Ability to kill certain cells spontaneously without interacting with lymphocytes or antigens.

• Produce interferon that inhibits viral replication

• Numbers decreased in cancer patients and also related to the severity of the illness

• Bone marrow and thyroid are considered primary lymphoid organs.

• Immune responses normally happen in lymph nodes / spleen –secondary lymphoid tissue

Lymph node architecture • Approx. 600 in the human body

• T & B cells occupy different compartments of the lymph node

• Inner cortex contains T-cell and dendritic cells

• Outer cortex contains B-cells

• Lymph nodes act as a filtering system for the lymph fluid

• Due to the flow of lymph – allows for multiple filtering events within individual nodes

HaematopoiesisHaematopoiesisPluripotentPluripotentStem CellStem Cell

CFU-BlastCFU-Blastflkflk-2/-2/fltflt-3-3 ligand ligand

SCFSCF

CFU-GEMMCFU-GEMM Lymphoid Ste m CellLymphoid Ste m Cell

BFU-EBFU-E

CFU-ECFU-E


RedRed


CFU-MegCFU-Meg



CFU-GMCFU-GM

CFU-MCFU-M

MonocyteMonocyte


CFU-GCFU-G




Bas ophilBas ophil




SCFSCFIL-3IL-3

GM-CSFGM-CSFEPOEPO

IL-3IL-3GM-CSFGM-CSF

G-CSFG-CSF



PrecursorPrecursor


CellCell



SCFSCFIL-3IL-3

MGDF/TPOMGDF/TPOSCFSCFIL-3IL-3

SCFSCFIL-3IL-3

flkflk-2/-2/fltflt-3-3 ligand ligand

SCFSCFIL-3IL-3

SCFSCFIL-3IL-3

CFU-MastCFU-Mast

SCFSCFIL-3IL-3

SCFSCFIL-3IL-3

GM-CSFGM-CSFIL-11IL-11IL-6IL-6

MGDF/TPOMGDF/TPO

IL-7IL-7


EPOEPO


G-CSFG-CSF


M-CSFM-CSF


IL-3IL-3 IL-3IL-3SCFSCF

IL-6IL-6 IL-2IL-2IL-7IL-7

SCFSCFIL-2IL-2


flkflk-2/-2/fltflt-3-3 ligand ligand SCFSCF



SCFSCFflkflk-2/-2/fltflt-3-3

ligandligandIL-7IL-7


ligand ligandIL-7IL-7

GM-CSFGM-CSFM-CSFM-CSF

Pluripotent stem cell

CFU-GEMM

Myeloid Stem Cell

THYMUS

CD10 CD117

CD34 CD124

CD38 CD127

CD90* CD228

BFU-E

CD36

CD123

CD131

CD117s

CD297

CD324CFU-Meg

CD41 CD42d CD110

CD42a CD49f CD123

CD42b (CD51) CD131

CD42c CD61 CD203c

Platelets

CFU-G

Monocyte

Macrophage

Promonocyte

Neutrophil

Antigen Expression & Haematopoiesis

CFU-Eo

Eosinophil

Basophil

Intermediate B-Cell

CD90* CD243

CD110* CD277

CD117 CD318*

CD123 CD338

CD135*

CD33 CD112* CD133* CD227*

CD34 CD117 CD173* CD228

CD110* CD123 CD174* CD280

CD111* CD131 CD176

B

L

O

O

D

B

O

N

E

M

A

R

R

O

W

CD33

CD34

CD123

CD131

CD297

CD324

CD35 CD236R

CD44 CD238

CD55 CD239

CD59 CD240CE

CD147 CD240D

CD173 CD241

CD223 CD240

CD234 CD297

CD235a

CD235b

CD236

CFU-E

Erythrocyte

CD34

CD110

CD123

Megakaryocyte

CD9 (CD51)

CD117 CD60a

CD23 CD61

CD31 CD84

CD36 CD92

CD41 CD109

CD42a (CD110)

CD42b CD147

CD42c CD151

CD42d CD173

CD49b CD226

CD49f

Activated Platelets

CD62P CD107a

CD63 CD107b

CFU-GM

Myelomonocytic Stem Cell

CFU-M

Myelocyte

CD13 CD115

CD15 CD116

CD33 CD123

CD111

CD131

112

CD13 CD112

CD14 CD115

(CD15*) CD116

CD 33 CD123

CD111 CD131

(CD4) (CD45RA) CD98 CD162 CD226

CD9 (CD45RB) CD101 CD163 CD277

CD11b CD49b CD102 CD164 CD281

CD11c CD49e CD111 CD168 CD282

CDw12 CD49f CD112 (CD170)

CD13 CD63 CD115 CD171 CD284*

CD14 CD64 CD116 CD172a (CD295)

CD15 CD65s CD119 CD172b CD300a

CD17 CD68 CD121b CD180 CD300c

(CD31) (CD74) CD123 CD184 CD300e

CD32 CD84 CD127 CD191 CD302

CD33 CD85 CD128b CD192 CD305

CD35 CD86 CD131 CD195 CD312

CD36 CD87 CD142* CDw198 CD317

CD38 CD89 CD147 CD206 CD322

(CD40) CD91 CD155 CDw210 CD328

CD43 CD92 CD156a CD213a1 CD329

(CD45RO) CD93 CD157 CD213a2

T

I

S

S

U

E

All Leucocytes

CD11a CD50 CD100 CD217 CD262

CD18 CD53 CD118 CD220 CD263

CD29 CD54 CD120a CD222 CD264

CD44 CD55 CD120b CD224 CD298

CD45 CD58 CD126 CD225 CD321

CD46 CD59 CD132 CD230

CD47 CD62L CD148 CD232

CD74R CD82 CD156b CD261

Endothelial Cells

CD54 CD121a CD147 CD249

CD62e CD124 CD152 CD252

CD92 CD140b* CD157 CD256*

CD30 CD141 CD166 CD280*

CD102 CD142* CD192 CD293*

CD105 CD143* CD201* CD309

CD106 CD144 CD202b CD322

CD109 CDw145 CD213a1 CD325

CD116 CD146 CD213a2

CD11c CD36 CD74 CD155 CDw210

CD14 CD45RO CD87 CD156a CD280*

CD16 CD45RB CD88 CD169* CD312

CD26 CD63 CD101* CD170*

CD31 CD68 CD119 CD204

CD32 CD71 CD121b CD206

Activated

Macrophage

CD23 CD25

CD69 CD105

CD13 CD112 CD131

CD33 CD115 CD280

CD34 CD116

CD111 CDw123

CD13 CD112

CD15 CD116

CD33 CD123

CD111

CD131

CD13 CD114

(CD15*) CD116

(CD33) CD123

CD111 CD131

CD112

CD10 CD66a CD131

CD15s CD66d CD157

CD16b CD89 CD170

CD17 CD92 CD177*

CD24 CD93 CD181

CD32 CD111 CD281

CD35 CD112 CD182

CD43 CD114 CD312

CD65 CD116

CD65s CD123

CD13

CD33

CD34

CD116

CD123

CD131

CD11b CD35

CD13 CD114

(CD15*) CD116

CD32 CD131

CD33Myelocyte

CD9 CD35 CD131

CD11b CD43 CD193

CD15 CD114 CD218a

CD24 CD116 CD218b

CD32 CD125 CD294

CFU-Bas

CD34

CD12

3

Myelocyte

(CD15*

) CD33

CD114

CD123

CD9 CD43 CD192

CD17 CD114 CD193

CD25 CD125 CD203c

CD33 CD131 CD294

CD38 CD154

Granulocytes

CD11b CD13 CD43 (CD63) CD87 (CD98) CD156a CD329

CD11c (CD14*) CD45RO CD66b CD88 CD101 CD182

CDw12 CD31 CD53* CD66c CD114 CD123 CD302

Activated Neutrophil

+ CD64 CD66

Activated Eosinophil

+ CD23 CD64 CD66

Activated Basophil

+ CD64 CD66

Lymphoid Stem

Cell

MYELOIDLYMPHOID

PRO-B CELL

Pre-Pre-B Cell

Pre-B Cell

Early B Cell

Mature B Cell

Activated B Cell

Lymph Node (also found in Bone Marrow)

Immunoblast

CD10 CD24 CD72 CD139

CD19 CD37 CD74 CD275

CD20 (CD39) CD79a CD316


Lymphoplasmacytoid Cell


CD20 CD79a CD275 CD317

Plasma Cell

CD38 CD269

CD79a CD275

CD126 CD316

CD138 CD317

CD – strong expression BFU-E – burst forming unit

–

(CD) - Weak expression Erythroid precursor

* - Subset expression E - Erythroid

CD-cy - cytoplasmic expression Eo - Eosinophil

CFU – colony forming unit G - Granulocyte

CFU-GM – colony forming unit Meg - Megakaryocyte

Granulocyte – Monocyte M - Monocyte

common precursor

K

E

Y

Reticulocyte

CD19 CD79b

CD22 CD124

CD24 CD127

CD34 CD179a

CD38 CD179b

CD72 CD317

CD79a

CD10 CD79a

CD19 CD79b

CD20 CD124

CD22 CD179a

CD24 CD179b

CD34 CD317

CD72

CD9 CD40 CD179b

CD10 CD72 (CD267)

CD19 CD74 (CD268)

CD20 CD79a CD(269)

CD22 CD79b CD275

CD24 CD124 CD316

CD38 CD179A CD317

CD19 CD40 (CD267)

CD20 CD72 CD268

CD22 CD74 CD269

CD24 CD79a CD275

CD37 CD79b CD316

(CD39) CD124 CD317

CD19 CD52 CD124

CD20 CD72 CDw210

CD21 CD74 (CD267)

CD22 CD75 CD268

CD24 CD75s CD269

CD32 CD79a CD275

CD35 CD79b CD316

CD37 CD80* CD317

CD40 (CD85)

CD48 CD99

CD5 CD48 CD79b CD180* CD268

CD19 CD49b CD80* CDw210 (CD269)

CD20 CD49c CD84 CD213a1 (CD275)

CD21 CD49d (CD85) CD213a2 CD277

CD22 CD52 (CD98) CD(229) CD305

CD24 CD72 CD99 CD185 (CD307)

CD32 CD74 CD102 CD192 CD316

CD35 CD75* CD119 CD196 CD317

CD37 CD75*s CD121b CD218a

CD319*

(CD39) CD78 CD124 CD218b CD322

CD40 CD79a CD171* (CD267) CD327

CD23 CD30 CD70 CD86 CD268 CD307

CD25 CD38 CD71 CD166 CD275 CD316

CD26 CD60b CD80 CD252 CD279 CD317

CD28 CD69 (CD83) CD253 CD289

LGL

(Large Granular

Lymphocyte /

NULL Cell / NK Cell

(Natural Killer Cell)

(Also found in tissues)CD2* CD56 CD160*

CD7* CD57 CD161

CD8* CD69 CD162R*

CD11b CD94 CDw210

CD11c CD122 CD226

CD16 CD158a CD244

CD35* CD158b CD247

CD48 CD159

Subcortical Thymocyte

Cortical Thymocyte

Medullary

Thymocyte

CD4

Medullary

Thymocyte

CD8

CD2 CD8

CD4 CD38

CD5 CD200

CD7

CD1a CD7

CD1b CD8

CD1c CD38

CD2 CD52

CD3 CD165

CD4 CD200

CD5

CD 2 CD52

CD3 CD69

CD5 CD99

CD6 CD121a

CD7 CD127

CD27 CD150

CD28 CD155

(CD38) CD165

CD48 CD166*

(CD49d) CD200

(CD49f)

+ +

Suppressor /

Inducer

T Lymphocyte

Cytotoxic /

Suppressor T

Lymphocyte

CD4+

CD45RA

CD8+

CD2 CD73 CD150a*

CD3 CD75s CD150b*

CD5 (CD75*) CD161

CD6* CD94* CD164

CD7 CD98 CD171*

CD11c* CD99 CD172a*

(CD27*) CD101* CD172g*

CD28* CD102 CD181*

CD31 CD103 CD182*

CD35 CD94* CD184*

(CD37) CD98 CD185*

CD43 CD99 CD186*

CD45RB* CD101* CD191

CD45RC* CD102 CD192*

CD48 CD103* CD193*

CD49d CD121a CD195*

CD(49f) CD122* CD196*

CD57* CD124 CDw198*

CD60a CD137* CDw199*

CD60c CD147* CDw210

(CD70) CD150 CD218a

+ +

Helper / Inducer

T Lymphocyte

Activated T Cell

CD4

CD45RO

CD197

CD272*

CD294*

CD8

CD2R CD49b CD71 CD109 CD154 CD223 CD267

CD25 CD49e CD(CD83) CD134* CD166 CD273

CD26 CD49f CD87 CD146 CD178 CD253 CD274

CD30 CD69 CD96 CD152 CD183 CD254 CD278

CD38 CD70 CD108 CD153 CD212 CD258 CD279

Reference1. Human CD Antigen Expression; Updated 2006; AbD Serotec (poster)

2. New listing of Human Leucocyte Differentiation Antigens

Update from 5th International Conference, Boston, 1993; Serotec (poster)

Dendritic Cells

CD85 CD206* CD258* CD277 CD303*

CD172b CD 207* CD265 CD283 CD304*

CD180 CD208* CD271* CD289* CD312*

CD187 CD209* CD273 CD300a CD317

CD193 CD218a* CD274 CD300b CD319*

CD196 CD218b* CD275 CD301* CD320*

CD205 CD252 CD276a* CD302

+

CD90 CD140b CD248 CD271 CD283 CD332 CD334

CD121a CD166 CD254 CD280 CD331 CD333 CD339

CD218b CD296

CD226 CD305

(CD229) CD316

CD244* CD317

CD245* CD319*

CD247 CD322*

CD277 CD328

Stromal Cells

M3

M2

M1

M4

M5

M6M7

Immunity

• Natural Immunity (Innate)

Native or innate resistance is not produced by the immune system

natural immunity present at birth

• Acquired Immunity (Adaptive)

gained after birth as a result of the immune response

active or passive, dependant on the immune response has been produced by host or donor

Active acquired immunity is produced by the host after either natural exposure to an antigen or immunization

Passive acquired immunity does not involve the host’s immune response. Antibodies are transferred to the recipient - maternal antibodies

Innate Immunity

• First line defense

Skin / epidermis

Mucous membranes

Hairs & cilia of the nose & respiratory tract

Lacrimal apparatus – tears & lysozymes

Saliva

Flow of urine

Vaginal secretions

Defecation and vomiting – expel microbes

Sebum in the sebaceous glands – keep skin acid

Perspiration

Gastric juices

Innate Immunity• Second line defences

Interferons Produced in lymphocytes / macrophages / fibroblasts

May diffuse interferon to neighbour cells

Complement

Iron-binding proteins Inhibit growth of some bacteria

Antimicrobial proteins Broad spectrum antimicrobial activity

Attract dendritic cells and mast cells

Natural Killer cells and phagocytes NK cells about 5-10% of lymphocytes

Non-Specific Resistance

• Inflammation Confines and destroys microbes and repairs tissues

• Fever Inhibits microbial growth and speeds up body reactions

that aides repair

Adaptive Immunity• Cell-mediated immunity (cells attacking cells)

Cytotoxic T-cells directly attack invading antigens

Intercellular pathogens (bacteria / virus / fungi inside the cell)

Some cancer cells

Foreign tissue transplants

• Antibody-mediated immunity B cells transform into plasma cells synthesise and secrete specific

proteins (antibodies or immunoglobulins).

A given antibody can bind and inactivate a specific antigen

Extracellular pathogens (virus / bacteria / fungi in body fluids outside the cells)

• Cell-mediated and antibody mediated immune responses often co-exist together to get rid of large numbers of antigen

Specific Immunity• T cell

• B cells

• macrophages

• Responses rely on the ability of cells to recognize specific antigens

• Relates to the specific fit between antigenic determinant sites of antigens and variable portions of antibodies

• Macrophages present antigens to T&B cells

• During this presentation macrophages release Interleukin 1, a powerful protein (cytokine) that induces proliferation of T&B cells

• Once active they in turn induce macrophages to participate in destruction of antigens

Cellular Immunity

• Lymphocytes enter thymus gland and exit as immature, but antigenically committed T-Lymphocytes

• migrate to lymph tissue and mature

• circulate in blood and meet a foreign antigen they are capable of binding with, stimulated to proliferate

• all cells produced are able to recognise the same antigen

• proliferation is antigen not thymus driven

• sub-populations of the immature T cells produce mature T cells having different function (cytotoxicity, memory, helper, or suppressor function)

• end result is a large number of T cells capable of acting against the same antigen in a variety of ways

Humoral Immunity

Immunoglobulins

• Antibodies or immunoglobulins are serum glycoproteins produced by plasma cells (mature B lymphocytes) in response to a challenge by an immunogen (an antigen that can induce the formation of components of the immune system I.e. maturation of T&B cells)

• Immunoglobulin is used to denote all molecules of this type

• Antibodies are immunoglobulins known to have specificity for a particular antigen.

• Molecular classes of immunoglobulins IgG, IgA, IgM, IgE, IgD. Within in each class are distinct subtypes

• Response are triggered in circulating mature immunoglobulin secreting and a set of long lived memory cells

Antibody

Structure

• antibody molecule consists of four polypeptide chains

two identical light chains (200 amino acids)

two identical heavy chains (400 amino acids)

the antibody consists of identical halves held together by disulfide bonds (S-S)

both chains divided into a variable and constant region

variable region has a large number of amino acid differences and attach specifically to a particular type of antigen

the remainder is the constant region, which is the same for all antibodies of the same class, but differs between classes, therefore able to distinguish classes

Immunoglobulin

MabThera®: A Mouse/Human Chimeric MoAb(Roche Pharmaceuticals)

Murine variable regions bind

specifically to CD20 on B cells

Human kappa constant regions

Human IgG1 Fc domain works in synergy

with human effector mechanisms

Chimeric IgG1

Adapted from Rybak et al. Proc Natl Acad Sci USA. 1992;89:3165.

Interaction of MabThera®

With Host Immune Effector Cells(Roche Pharmaceuticals)

Adapted from Male et al. Advanced Immunology. 1996;1:1.

Malignant

B cellCD20

MabThera®MabThera®

CD20

ComplementKiller

leukocyte

Inflammation

• Biochemical and cellular process that occurs in vascularized tissues

• Classic signs of inflammation

redness - (rubor)

swelling - (tumor)

heat - (calor)

pain - (dolor)

loss of function - (function laesa)

• Some aspects of inflammation may be reduced when patients are neutropaenic

Complement System

• Consists of ten proteins, that make up 10% of the serum proteins in circulation

• Components are involved in nearly every phase of the inflammation response

• The final proteins in the cascade are able to directly kill microorganisms

• Can be activated by antigen-antibody complexes and also products released from invading bacteria and other plasma proteins

• Nonspecific mechanism of self defense

• Complement cascade has two pathways: classical & alternate

Complement CascadeANTIGEN-ANTIBODY COMPLEXES Polysaccharides from bacterial cell walls

C1, q,r,s

C1, 4b

C1,4b, 2b

C1, 4b, 2a, 3b

C3b

C3b, B

C3b, B

C3b, B, P

C3b, B, P, C3b

C5b

C6

Lysis of a target cell

C7

C8

C9

Terminal

components

C4Anaphylatoxin C4a

Kininlike activity C2a C2

Anaphylatoxin C3a C3

Anaphylatoxin C5a

C5

Classical Pathway Alternative Pathway

Chemotactic factor

Factor B

Factor D

Properdin

C3b

Interaction of the Complement, Clotting Kinin& Fibrinolytic (plasmin systems)

C5, 6, 7, 8, 9C6, C7, C7, C8, C9

C5 + C5aC5

C3b + C3aC3

C4, 2 C4, 2

C1 C1 Complement System

Intrinsic pathway

Prothrombin

Thrombin

Fibrinogen

Fibrin

Plasmin

Plasminogen

Fibrinopeptides

Hageman Factor Xll

Xlla

Prekallikerin

activator

Prekallikrein

Kallikrein

KININ SYSTEMCLOTTING SYSTEM

Kininogen

Bradykinin

Bold arrows denote activation factors within a system

Thin arrows denote where a particular factor activates

another system

Complement System

Classical Pathway

• antigen-antibody complexes containing IgG / IgM

• antibody Fc unit binds to C1 (has 6 sites for binding)

• Activation of C1 results in the sequential enzymatic activation of all other components of the cascade

Alternate Pathway

• several non-antibody mediated avenues of entrance into the complement pathway

• polysaccharides from bacterial cell walls

• both pathways meet at C5b to access C6,C7,C8,C9 for lysis of target cell

Future Challenges• Rapidly changing clinical interventions

• Identification of new mutations and immune receptors that may be a target for new treatments CTLA-4; immune checkpoint that when bound to CD80 & CD86 on antigen

presenting cells; CTLA-4 can act as an off switch to down regulate the immune response

PD-1; expressed on activated T-cells, B-cells and macrophages. May inhibit T-cell activation

Known effect in melanoma / H&N SCC / CRC. Now being investigated in haematological malignancies

Hodgkin’s /

• New treatments may have specific side effect profiles

• ONS –Voice, August 2018 (Conforti et al) – males have greater survival benefit from Immune Checkpoint Inhibitors (11,315)

• Cost and treatment time frames are a significant community issue when approved for PBS ($100,00 to $150,000 per patient per year)

Future Challenges• CAR T-Cell therapies

• Phase 1&2 trials

• Not 1st line treatment

• Target specific CD antigens

• Potential significant side effects Cytokine release syndrome (similar syndrome identified in

Allogeneic stem cell transplant)

• Significant cost issues that will improve with further development and refinement – approx. $500,000 per patient

Nursing Management

• Nurses need to have intimate knowledge

of the disease being treated

Specific diseases / treatments may have specific variations

Autologous vs. Allogeneic transplant

Allogeneic sibling vs. Unrelated vs. Cord

the treatments themselves

disease trajectory

Diagnosis / treatment / maintenance / relapse / survivorship / palliation

changes in patient’s condition

assessment of patients

‘gut’ instinct only works some times

Need enhanced clinical assessment skill to confirm and follow-up

need to clearly identify assessments and communicate with medical staff

aware of the aims of treatment

Nursing Management • Nurses are at the bedside 24 hours a day caring for patients

• The nursing team does reflect on patients and how the treatments are progressing

• There will always be difficult days for most patients

• There will be difficult days for nurses individually

Personal and professional

• We need to remember that a significant number of patients can also be in the outpatient setting

• Need to listen and be guided by family & friends; but also involve the patient

HaematopoiesisHaematopoiesisPluripotentPluripotentStem CellStem Cell

CFU-BlastCFU-Blastflkflk-2/-2/fltflt-3-3 ligand ligand

SCFSCF

CFU-GEMMCFU-GEMM Lymphoid Ste m CellLymphoid Ste m Cell

BFU-EBFU-E

CFU-ECFU-E


RedRed


CFU-MegCFU-Meg



CFU-GMCFU-GM

CFU-MCFU-M

MonocyteMonocyte


CFU-GCFU-G




Bas ophilBas ophil




SCFSCFIL-3IL-3

GM-CSFGM-CSFEPOEPO


G-CSFG-CSF



PrecursorPrecursor


CellCell



SCFSCFIL-3IL-3

MGDF/TPOMGDF/TPOSCFSCFIL-3IL-3

SCFSCFIL-3IL-3

flkflk-2/-2/fltflt-3-3 ligand ligand

SCFSCFIL-3IL-3

SCFSCFIL-3IL-3

CFU-MastCFU-Mast

SCFSCFIL-3IL-3

SCFSCFIL-3IL-3

GM-CSFGM-CSFIL-11IL-11IL-6IL-6

MGDF/TPOMGDF/TPO

IL-7IL-7


EPOEPO


G-CSFG-CSF


M-CSFM-CSF


IL-3IL-3 IL-3IL-3SCFSCF

IL-6IL-6 IL-2IL-2IL-7IL-7

SCFSCFIL-2IL-2






ligandligandIL-7IL-7


ligand ligandIL-7IL-7

GM-CSFGM-CSFM-CSFM-CSF

The Home Supervisor

Haematology nurses MAKE a differenceAs individual’s – rely on our own developed clinical skills and learning

As a professional team – we support each otherAs part of the ‘whole patient care team’

At 3am you may be their last line of defence

Resources• eviQ Education

• EdCan

• Oncology Nursing Society (ONS – USA)

• National Comprehensive Cancer Network

• Clinical Care Options

• Medscape

• Roche Pharmaceuticals

• AstraZeneca

• Other pharmaceutical resources Have access to journals & learning information

IMMUNITY

IS NOT JUST

NEUTROPAENIA

References

• Clarke. S. and Li, B. (2017) Fast Facts: Immuno-Oncology, Health Press, UK. (Astra-Zenica).

• Hoffbrand, A.C; Higgs, D.R; Keeling. D.M & Metha.A.B (2016) Post Graduate Haematology, 7th Edition. Wiley-Blackwell, Oxford.

• Swerdlow, S.H; Campo, E; Harris, N.L; Jaffe, E.S; Pileri, S.A; Stein, H. and Thiele, J. (2017) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th Edition. International Agency for Research on Cancer. Lyon, France.

• Tortora. G.J. and Derrickson. B. (2011) Principles of Anatomy & Physiology, 13th Edition. Wiley-Blackwell, Oxford.

Documents

Immunity Overview Blood 2018 Nurses Education Day · 2018. 10. 23. · T-cells (cell mediated immunity) Natural killer cells The Amgen slide identifies the NK cell as a myeloid differentiating