경희대학교 의과대학·의학전문대학원

전체 글

(1)

혈액학 서론

경희의대 종양혈액내과

조경삼

(2)

Stem Cell (

줄기세포 , 모세포 )

• A cell with a unique capacity to produce unaltered

daughter cells (

self renewal

) and to generate

specialized cell types (

potency

) :

자기복제 , 분화

Symmetrical or Asymmetrical

(3)

전능

원능

(4)

• Stem cells as therapy (either to replace cell lines that have been lost or destroyed, or to modify the behavior of other cells [mesenchymal stem cell]) :

•Stem cells as targets of drug therapy

• Stem cells to generate differentiated tissue for in vitro study of disease models for drug development

(5)
(6)

Challenges in clinical use of stem cell

• Ethical problems :

– Embryonic stem cell

– iPS (induced pluripotent stem cell) – Adult stem cell (multipotent)

• 임상적용의 필요 조건 – 충분한 세포수 확보 – 필요한 세포로의 분화력 – 충분한 기간 동안의 기능유지 ( 생존력 ) – 숙주 조직과의 통합 조정력 – 해로운 영향력 배제 : teratoma, malignancy

(7)

HSC(hematopoietic stem cell)

• 0.005% of the bone marrow cells CD34+ cell : 2 – 5%

• Stem cell -- pluripotent cell -- progenitor cell • 실험적 근거

– Radioprotection in irradiated animal

– LTRC: long-term multilineage reconstitution – Formation of CFU-s

• 임상 적용

– Stem cell transplantation

– Plerixfor (Mozobil) : CXCR4 antagonist Stem cell mobilization in

(8)

Identification of stem and progenitor cells

• 중간 크기 정도의 림프구 모양

• Functional assay or surface antigenic

characteristics

– In vitro assays : LTC-IC; CAFC; HPP-CFC;

CFU-GEMM

– Cell surface antigenic markers :

• CD34+, CD38-, Thy-1+, CD133+, c-kit+, CD33-, Lin-,

HLA-DR-– Rhodamine 123 (Rh-123-low), Hoechst 33342,

(9)
(10)
(11)
(12)
(13)
(14)

Extramedullary hematopoiesis BM aspiration and biopsy

(15)

BM anatomy and microenvironment

• Hematopoietic stem cell require cellular and soluble growth factor support

• Cellular component : surrounding bone, stromal cells and

microenvironment

• Microenvironment : a vast network of vascular channels or sinusoids between which float fronds of hematopoietic cells, including fat cells.

• Stromal cells : fibroblastoid cells, endothelial cells, and macrophages; these cells provide cell-cell contact support to HSC and growth factors

• Stem cell niche in BM :

– Endosteal niche : self-renewal

(16)
(17)
(18)

Peritubular capillary lining cell, hepatocyte

(Half clearance time: 6 – 9 hr, 10 – 25 U/L)

(19)

20 회의 세포분열 : 106 성숙세포

적혈구 : 5 일 혈소판 : 7 일

(20)

Blood cells

• 혈액세포

– RBC: oxygen delivery

– WBC: host defense (bacteria) – Platelet: hemostasis

• 수명

– RBC: 120 days

– Granulocyte: 6-8 h; days in tissue

– Monocyte(macrophage): weeks to years

– Platelet: 10 days

– Lymphocyte: variable, hours up to several years

(21)

Hematopoiesis(

조혈 )

• 조혈 자극

– RBC: tissue oxygen level

– WBC: noxious foreign stimuli (bacteria)

– Platelet: blood loss, tissue damage, platelet deficiency

• 생산량 : Over 500 billion cells per day

– RBC: 2 billion/Kg ; 10 billion/hr

– Platelet: 7 billion/Kg

– Neutrophil: 0.85 billion/Kg

• 성숙 조혈세포 Erythrocyte, neutrophil, eosinophil, basophil, monocyte, B cell, T cell, NK cell, dendritic cell

(22)

Clinical implications of stem cell biology

• Diagnosis of hematologic diseases

• Stem cell transplantation

• Gene therapy

• Therapeutic use of hematopoietic growth

(23)

Diagnosis (molecular biology)

• Detection of specific mutations in populations and famillies at risk:

– carrier detection of sickle cell anemia

– estimation of specific-thalassemia mutations in population

• Prenatal diagnosis of disease:

– beta thalassemia, sickle cell anemia

• Detection of MRD:

– t(14;18), t(9;22), t(15;17), ARG rearrangements

• Detection of clonality and lineage :

– ARG rearrangements, cell surface marker

• Distinguishing genotypes of hematopoietic cells:

(24)

Detection of MRD

(CR : complete remission)

• Hematologic : morphologic

• Cytogenetic :

– chromosome analysis

– FISH

• Cell surface marker :

– Flow cytometry (multi-color)

• Molecular biology :

(25)

Stem cell transplantation

• Autologous SCT:

– high dose chemotheray

– tumor cell contamination

• Allogeneic SCT: Immunotherapy

– GVHD

– GVT

• PBSCT

(26)

HGF

• Erythropoiesis stimulating agent :

Epo

• Thrombopoiesis stimulating agents :

– Tpo

– Second generation : Romiplostim, Eltrombopag

• Leucopoiesis stimulating agents

– G-CSF, GM-CSF

• Neutropenia, mobilization

• bone pain, rash fever, fatigue, anorexia, phlebitis, thrombosis,

capillary leak syndrome

• Others :

– II-3, IL-6, IL-1, Pixy-321(IL-3+GM-CSF) – In vitro expansion of HSC

(27)

Clinical use of HGF

• Transient bone marrow failure following chemotherapy • Hematopoietic stem cell and progenitor cell mobilization • Recovery from hematopoietic cell transplantation

• Myelodysplastic syndrome • Aplastic anemia

• Some forms of neutropenia

• Inherited bone marrow failure syndromes • HIV infection-associated neutropenia

• Chronic anemias (eg, renal failure, prematurity,

chronic disease/inflammation, HIV infection) • Reducing the need for perioperative blood transfus

(28)

Potential toxicities of the recombinant HGFs

• Transient leukopenia

• Systemic reactions (eg, flu-like symptoms,

capillary leak, hypertension, thrombosis)

• Production of deleterious neutralizing antibodies

• Possible stimulation of malignancy

• Possible enhancement of HIV replication

(29)
(30)
(31)

Field of Hematology

• RBC

• WBC

• Platelet

• Bone marrow (stem cell)

• Coagulation factors

• Stem cell transplantation

• Transfusion

(32)

Erythroid

• Anemia

– Production defect : iron deficiency anemia

– Destruction : hemolytic anemia

– Loss : hemorrhage

• Erythrocytosis

– Primary : polycythemia vera : MPN

– Secondary erythrocytosis

(33)

WBC

• Leucocytosis

– Primary : MPN, leukemia

– Secondary : leukemoid reaction

• Leucopenia

– Primary : AA, MDS

– Secondary : drug, infection

• Functional defect

– Congenital

– Acquired

(34)

Platelets

• Thrombocytosis

– Primary : MPN

– Secondary : infection, Fe deficiency

• Thrombocytopenia

– Production : aplastic anemia

– Destruction : ITP, DIC

• Functional defects :

– Congenital : thrombasthenia

– Acquired

(35)

Bone marrow (Stem cell)

• Tumors of hematopoietic and lymphoid tissues

(WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues (2008))

– Myeloid neoplasm

– Acute leukemia of ambiguous lineage

– Lymphoid neoplasm

– Histiocytic and dendritic cell neoplasm

• Hypoplastic anemia

– Idiopathic – Drug

(36)

Others

• Coagulation factors

– Deficiency :

• Congenital • Acquired

– Thrombosis

• Stem cell transplantation

– Allogeneic

– Autologous

(37)

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