Week 13 - Bone Marrow Transplant and GVHD

Question 1

Sources of Stem/Progenitor Cells - Adult Stem Cells

Answer 1

Largest reservoir in bone marrow
Can be isolated from peripheral blood, skin, brain, prostate, muscle

Question 2

Sources of Stem/Progenitor Cells - Cord Blood Stem Cells

Answer 2

From blood in the umbilical cord and placenta after delivery
Most often used in children and small adults

Question 3

Sources of Stem/Progenitor Cells - Embryonic Stem Cells

Answer 3

From fertilised embryos during early phases of development

Question 4

Graft Sources

Answer 4

Autologous: from the patient
Syngeneic: from an identical twin
Allogeneic: from another person

Question 5

Autologous Transplant

Answer 5

Patient’s own cells
Rescue from high dose chemotherapy
Must NOT have evidence of disease in the blood or bone marrow
Transplant related mortality (TRM) low = <5%
Relapse rates higher (than allogeneic transplant) depending on the disease
No graft versus host disease
No graft versus tumour effects

Question 6

Allogeneic Transplants - Matched Unrelated Donor

Answer 6

High transplant related mortality (TRM) = 30-50%
Graft versus host disease (GVHD)
Lower relapse rates due to graft versus tumour effects

Question 7

Allogeneic Transplants - Matched Related Donor (Sibling)

Answer 7

25% chance a sibling will be a match
The more siblings a patient has the better chance for a match

Question 8

Key Events for Stem Cell Transplant

Answer 8

1. Donor selection
   - based on tissue typing of 6-10 HLA antigens in allogeneic transplantation
2. Harvesting stem cells from healthy donor
   - bone marrow harvest or pheresis of peripheral blood
3. Preparative regimen for patient
   - chemotherapy + radiation for disease ablation and immune suppression
4. Stem cell intravenous infusion into patient
5. Post-transplant supportive care
   - autologous 100 days
   - allogeneic 180 days or longer for tolerance to develop

Question 9

Preparative Regimens (Conditioning)

Answer 9

1. Myeloablation
   - high doses of chemotherapy +/- radiation to destroy cancer cells
2. Stem cell infusion
3. Maintain transplanted cells with immunosuppressant drugs

Question 10

Aims of Myeloablation

Answer 10

To eliminate malignancy
To generate immunosuppression to allow engraftment
To decrease host versus graft effects

Question 11

Preparative Regimens: Non-Myeloablative Conditioning

Answer 11

Low dose chemotherapy and/or irradiation
Provides sufficient immunosuppression to allow donor cell engraftment
Less injury to organs, fewer infections, fewer transfusions
Higher relapse rates
May have mixed chimerism
Aims to enable donor cells (graft) to eradicate the cancer - not the chemotherapy
Mediated by donor allogeneic T-cells

Question 12

What is Non-Myeloablative Conditioning Better For?

Answer 12

Slow growing cancers
- chronic lymphocytic leukaemia (CLL)
- non-Hodgkin lymphomas (NHL)
Older patients or patients with co-morbid condition

Question 13

What Can a Patient Expect After Stem Cell Transplant?

Answer 13

Bone marrow cellularity decreased months post transplant
Immunologic reconstruction over 100 days post transplant
Graft-versus-host disease (GVHD) delays immune reconstitution
Immune deficits

Question 14

Immune Deficits After Stem Cell Transplantation

Answer 14

T cell and B cell dysfunction
Low Ig levels for 3 months
Normal IgG and IgM by one year
Normal IgA by two years
Predisposed to fungal, viral and bacterial infection

Question 15

What Happens to Transplanted Stem Cells?

Answer 15

“Home” through blood, across endothelial cells to bone marrow niches
Note bone marrow is ‘empty’ after chemo/irradiation
Recognise adhesion molecules and growth factors in bone marrow stroma
Proliferate until bone marrow is ‘full’ = homeostatic proliferation

Question 16

GVHD Prevalence

Answer 16

Despite immunosuppressive drugs - prevalence is high
40-60% in patients with an HLA-identical sibling donor
60-90% with a matched unrelated donor

Question 17

Factors Necessary for GVHD to Occur

Answer 17

Immunologically competent donor graft
Histo-incompatibility between donor and host
Immunologically incompetent host

Question 18

GVHD - Skin

Answer 18

Most frequently affected
Starts in upper body
Maculopapular rash to dermatitis - blisters & epidermal necrolysis
Histology: degeneration & apoptosis of basal cells, dyskeratosis & lymphocytic infiltration

Question 19

GVHD - Gastrointestinal Tract

Answer 19

Diarrhea, malaise and vomiting
Histology: e.g. grade 1 isolated crypt apoptosis

Question 20

GVHD - Liver

Answer 20

Jaundice and increased liver enzymes
Histology: bile ducts destroyed by infiltrating lymphocytes.

Question 21

Transplantation of (Allo)antigens - MHC Antigens

Answer 21

Main alloantigens of graft rejection
MHC class I on all cells
MHC class II on all APCs (Dendritic cells, B cells and macrophages)
MHC class I and II up-regulated on APC and tissue cells during inflammation
- become target antigens by allo-specific T cells

Question 21

Transplantation of (Allo)antigens - MHC Alloantigens

Answer 21

Cause fast and strong rejection by allo-specific T cells
Difference between HLA types is the main cause of human grafts rejection

Question 22

Transplantation of (Allo)antigens - Minor Histocompatibility Antigens (Also Alloantigens)

Answer 22

Cause slower and weaker graft rejection
- e.g. human ABO blood group antigens
- some tissue specific antigens - most in skin＞kidney＞heart＞pancreas ＞liver
- e.g. Vascular endothelial cell (VEC) antigen

Question 23

How do APCs Recognise Allogeneic MHC Molecules?

Answer 23

APCs process their own (self) MHC molecules - may also process MHC from dead cells
Place processed MHC peptides (alloantigen or allopeptide) onto intact MHC molecules
Move peptide/MHC complexes to cell surface
Donor APCs present allo-peptides to alloantigen-specific donor and host T cells
Host APC present ‘alloantigen’ to donor and host T cells

Question 24

How do T Cells Recognise Allogeneic MHC Molecules?

Answer 24

Donor T cells and recipient T cells that survived ablation
TCR recognises allopeptides in MHC molecules

Question 25

Graft-Versus Cancer (Malignancy) Effects

Answer 25

Lower incidence of leukemic relapse in patients who get acute or chronic GVHD
Higher relapse rates in syngeneic (e.g. identical twins) BM transplants (no GVHD)
High relapse rates in T cell depleted bone marrow transplants (no GVHD)

Question 26

Direct Presentation - Donor APC

Answer 26

Donor APC migrate to lymph nodes
Present alloantigen to allo-reactive host T cells = GVHD
Present tumour antigen to donor T cells = graft versus cancer response

Question 27

Indirect Presentation - Recipient (Host) APC

Answer 27

Host APCs migrate to lymph nodes
Present alloantigen to alloreactive donor T cells = GVHD
Present self antigen to host T cells = GVHD
Present tumour antigen to host T cells = graft versus cancer response

Question 28

What Happens when APCs are Activated?

Answer 28

Up-regulate MHC class I & II
Up-regulate co-stimulatory molecules CD80, etc,
Pick up dead or dying host tissue cells
Process tissue cells into peptides
Place peptides in MHC molecules
Present peptides to donor and recipient CD4+ and CD8+ T cells
Once activated both host and donor CD8+ T cells can attack host tissues

Question 29

Role of Activated CD4+ T Cells

Answer 29

Traffic to tissue site
Secrete cytokines
Macrophages activated and secrete more cytokines
Natural killer cells activated

Question 30

Model for GVHD

Answer 30

EXPLAIN FROM LECTURE