Week 13 - Bone Marrow Transplant and GVHD Flashcards
Sources of Stem/Progenitor Cells - Adult Stem Cells
Largest reservoir in bone marrow
Can be isolated from peripheral blood, skin, brain, prostate, muscle
Sources of Stem/Progenitor Cells - Cord Blood Stem Cells
From blood in the umbilical cord and placenta after delivery
Most often used in children and small adults
Sources of Stem/Progenitor Cells - Embryonic Stem Cells
From fertilised embryos during early phases of development
Graft Sources
Autologous: from the patient
Syngeneic: from an identical twin
Allogeneic: from another person
Autologous Transplant
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
Allogeneic Transplants - Matched Unrelated Donor
High transplant related mortality (TRM) = 30-50%
Graft versus host disease (GVHD)
Lower relapse rates due to graft versus tumour effects
Allogeneic Transplants - Matched Related Donor (Sibling)
25% chance a sibling will be a match
The more siblings a patient has the better chance for a match
Key Events for Stem Cell Transplant
- Donor selection
- based on tissue typing of 6-10 HLA antigens in allogeneic transplantation - Harvesting stem cells from healthy donor
- bone marrow harvest or pheresis of peripheral blood - Preparative regimen for patient
- chemotherapy + radiation for disease ablation and immune suppression - Stem cell intravenous infusion into patient
- Post-transplant supportive care
- autologous 100 days
- allogeneic 180 days or longer for tolerance to develop
Preparative Regimens (Conditioning)
- Myeloablation
- high doses of chemotherapy +/- radiation to destroy cancer cells - Stem cell infusion
- Maintain transplanted cells with immunosuppressant drugs
Aims of Myeloablation
To eliminate malignancy
To generate immunosuppression to allow engraftment
To decrease host versus graft effects
Preparative Regimens: Non-Myeloablative Conditioning
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
What is Non-Myeloablative Conditioning Better For?
Slow growing cancers
- chronic lymphocytic leukaemia (CLL)
- non-Hodgkin lymphomas (NHL)
Older patients or patients with co-morbid condition
What Can a Patient Expect After Stem Cell Transplant?
Bone marrow cellularity decreased months post transplant
Immunologic reconstruction over 100 days post transplant
Graft-versus-host disease (GVHD) delays immune reconstitution
Immune deficits
Immune Deficits After Stem Cell Transplantation
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
What Happens to Transplanted Stem Cells?
“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
GVHD Prevalence
Despite immunosuppressive drugs - prevalence is high
40-60% in patients with an HLA-identical sibling donor
60-90% with a matched unrelated donor
Factors Necessary for GVHD to Occur
Immunologically competent donor graft
Histo-incompatibility between donor and host
Immunologically incompetent host
GVHD - Skin
Most frequently affected
Starts in upper body
Maculopapular rash to dermatitis - blisters & epidermal necrolysis
Histology: degeneration & apoptosis of basal cells, dyskeratosis & lymphocytic infiltration
GVHD - Gastrointestinal Tract
Diarrhea, malaise and vomiting
Histology: e.g. grade 1 isolated crypt apoptosis
GVHD - Liver
Jaundice and increased liver enzymes
Histology: bile ducts destroyed by infiltrating lymphocytes.
Transplantation of (Allo)antigens - MHC Antigens
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
Transplantation of (Allo)antigens - MHC Alloantigens
Cause fast and strong rejection by allo-specific T cells
Difference between HLA types is the main cause of human grafts rejection
Transplantation of (Allo)antigens - Minor Histocompatibility Antigens (Also Alloantigens)
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
How do APCs Recognise Allogeneic MHC Molecules?
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
