Hematopoiesis, Stem cells, Bone Marrow transplant Flashcards
3 classes of proteins
Intracellular Transmembrane Secretory
NCE Drugs
New Chemical Entities traditional drugs, usually are agonists or antagonists of a ligand(secreted protein)/receptor (transmembrane protein) interaction or enzyme modulators
Biological Drugs
Recombinant Proteins (Secreted proteins that fail in certain diseases). • Insulin (Diabetes) • Erythropoietin (Anemia) – Monoclonal Antibodies: These are highly specific antibodies that bind secreted or transmembrane proteins
“New Wave” drugs
New therapeutics that involve isolation of blood cells with specific functions, modification in vitro, and re-administration to the patient to modify his/her immune response
Blood consists of…
45% cells – The bulk of the cells consist of red blood cells (erythrocytes) – Platelets and leukocytes (neutrophils, monocytes, basophils, eosinophils, lymphocytes) make up the remainder 55% plasma typical volume ~ 5L
hematopoiesis
formation of blood cells in the bone marrow The bone marrow contains hematopoietic stem cells and their progeny, and supporting tissues (stroma) that produce cytokines that promote their development “Dry bone marrow” very few blood cells suggests that hematopoeisis is deficient. 0 to 3 months in utero: mesoderm of yolk sac; 3 to 7 months in utero: liver is the main blood-forming organ with spleen contributing; 7 months and beyond: Bone marrow; 70% in pelvis, vertebrae, sternum
hematocrit
volume % of RBCs in blood Normal 37.5-50% (higher in men, 48%, than women, 38%)
neutrophil
aka Polymorphonuclear cell first responders to microbial invasion pus 50-70% of wbcs 3000-6000 per microliter blood # increase for infections # decrease for poisoning, leukemia, genetic disease, vit B12 deficiency, autoimmunity, chemotherapy
eosinophil
immune responses to parasites 1-4% of wbcs 150-300 per microliter blood # increase for parasite infestation
basophils
0-1% of wbcs 0-100 per microliter blood -contain vasoactive amines which participate in allergic responses -May be involved in resistance to bites from venomous animals # increase for chronic myelogenous leukemia
lymphocytes
20-40% of wbcs 1500-4000 per microliter blood B lymphocytes- produce antibodies. CD4 T lymphocytes- ‘directors of the orchestra’ of the immune system through cytokine production CD8 T lymphocytes- aka cytotoxic T cells, especially good at killing virus-infected cells # increase for leukemias, infections # decrease for immunodeficiency
monocytes
2-8% of wbcs 300-600 per microliter blood - These are more serious ‘defenders’ that come into play if the neutrophils cannot do the job, or, to clear the field of dead neutrophils. -Big participants in INFLAMMATION -differentiate into tissue resident macrophages or dendritic cells # increase for infections and chronic inflammation # decrease for leukemias, stress, glucocorticoids, genetic diseases
platelets
200,000-500,000 per microliter blood key role in coagulation
mast cell
granulated cells that contain histamine and heparin, an anticoagulant. Both cells also release histamine upon binding to immunoglobulin E very similar to basophils
stroma
supporting tissue of hematopoietic stem cells fat cells, fibroblasts, macrophages, endothelial cells
Hematopoietic stem cells
Pluripotent stem cells: self renewing; destruction can lead to pancytopenia -destroyed by radiation, infections (e.g. hepatitis C), chemical poisons and drugs. -Main cytokines supporting them: Stem cell factor, flt-3ligand CXCL12 Committed stem cells: do not self renew, committed to a particular lineage. -Cytokines Promoting their differentiation: IL3, GM-CSF, G-CSF, M-CSF, IL-7. -Think of them as ‘adolescent’ cells
pancytopenia
decrease in all blood cell lineages
cytokines
Small secreted proteins produced by many cell types that control inflammation, immune responses, and other important processes through their ability to induce differentiation and/or proliferation of certain cells
SCF
-produced by fibroblasts and endothelial cells - Ligand of c-kit (recepotor on HSC) -supports pluripotent hematopoietic stem cells - no SCF -> death by anemia
Interleukin 3
Supports stem cells and committed precursors
GM-CSF
Granulocyte-Monocyte Colony Stimulating Factor: Source: T cells, stromal cells; Supports growth of neutrophils and monocytes
G-CSF
Granulocyte Colony Stimulating Factor: Source: T cells, stromal cells; Supports differentiation and growth of neutrophils
M-CSF
Monocyte Colony Stimulating Factor: Source: T cells, stromal cells; Supports differentiation and growth of monocytes
EPO
Erythropoietin- Supports growth and terminal differentiation of RBC
iron
required for heme synthesis
folate
Vit B-12, required for DNA synthesis
Thrombopoietin
required for megakaryocyte (platelet) development.
CXCR4
A chemokine receptor that along with its ligand (CXCL12) plays a key role in maintaining the HSC in the bone marrow it is down-regulated during maturation until cell is released from stroma
bone marrow aspiration
Pelvis is the preferred site for bone marrow aspiration, sternum can also be used for obese pts
CD34+
a cell surface glycoprotein and functions as a cell-cell adhesion factor. It may also mediate the attachment of stem cells to bone marrow extracellular matrix or directly to stromal cells on HSCs
Ckit+
cell surface marker that identifies HSCs
Lin-
lack lineage markers on HSCs
pancytopenia
decreased numbers of white blood cells, red blood cells, platelets
leukopenia
decreased white blood cells
neutropenia
aka granulocytopenia, decreased neutrophils
monocytopenia
decreased monocytes
Eosinopenia
decreased eosinophils
Basocytopenia
(basopenia): decreased basophils.
Lymphopenia
decreased lymphocytes
Thrombocytopenia
decreased platelets
Erythropenia
decreased red blood cells
CYTOSIS
white blood cells above the normal values
plasma
all plasma proteins 7g/dL -albumin (4g/dL) -globulin -transferrin -ceruloplasmin
CFU-GEMM
-colony forming unit that generates myeloid cells -multipotential progenitor cells -give rise to granulocytes (neutrophils), erythrocytes (RBC), monocytes- macrophages, megakaryocytes- platelets, eosinophils, basophils NOT lymphocytes (CFU-L)
CFU-L
-aka lymphoblast -give rise to lymphocytes
reticulocyte
-RBC precursors that leave the BM, stay in blood for 1 day before maturing into RBC -contain cytoplasmic RNA which stain with supravital dyes giving a reticular pattern -nucleus is delete during last erythroblast stage (dead weight) before becoming a reticulocyte
Absolute Reticulocyte Count
retic% x RBC count
Reticulocyte Index
determines rate of RBC production retic%x(patient’s hematocrit/normal hematocrit)
Hematopoesis- image
