BENIN BLOOD & MARROW TRANSPLANT SOCIETY OF NIGERIA 15-27 JULY 2013. STEM CELL TRANSPLANT CENTRE,...

BENIN BLOOD & MARROW TRANSPLANT SOCIETY OF NIGERIA

15-27 JULY 2013. STEM CELL TRANSPLANT CENTRE, BENIN

Graft versus Host Disease in HSCT

Anthony Oyekunle FMCPath.

Senior Lecturer & Consultant Haematologist

Obafemi Awolowo University, Ile-Ife

Graft versus Host Disease in HSCT BENIN BLOOD & MARROW TRANSPLANT SOCIETY OF NIGERIA


Dr A A Oyekunle

What is GvHD? A cell-mediated reaction of donor origin

against recipient tissues It requires:

immunologically competent or T-cell replete donor graft tissue

immunologically incompetent or immuno-ablated recipient

recipient expressing tissue (MHC or mHC) antigens that are absent in the donor.



Dr A A Oyekunle

Basic Immunology Auditors - responsible for sifting through all

available info to find evidence of intrusion. Present data to Regulators and Enforcers.

Regulators - Reviews data presented by Auditors and contacts Enforcers. (includes prosecutors and defenders)

Enforcers - Kill things.



Dr A A Oyekunle

Auditors Dendritic cells B cells Macrophages Endothelial

cells Kupffer cells

Sample Outside Sample Inside Process

Specimen Present Data



Dr A A Oyekunle

Communicating Trouble

HLA Class I - i.e. HLA-A, B, C

HLA Class II - i.e. HLA - DR, DQ, DP

CD4

CD8

“Regulator”

“Enforcer”

Dendritic cellB cellMacrophage

“Meaning of Life”

“Trouble” signal



Dr A A Oyekunle

Pathogenesis of Acute GvHD

Culled from Hematopoietic Stem Cell Transplantation; ESH-EBMT (2008).



Dr A A Oyekunle

Clinical Features of Acute GvHD Risk Factors

HLA compatibility Gender mismatch: female

male Alloimmunization:

multiparity, transfusions SC source: PB>BM>CB Recipient age Conditioning GvH prophylaxis CMV positive Tissue injury

Signs/Symptoms Skin

Inflammatory rash

Gut Secretory diarrhea

Liver Cholestasis



Dr A A Oyekunle

Severity and Grading system (Glucksberg)

Culled from Hematopoietic Stem Cell Transplantation; ESH-EBMT (2008).



Dr A A Oyekunle

Why do HLA matching?

BMT = immune system transplant HLA molecules act as T cell

“superantigens” All somatic tissues express HLA class I Transferred T cell could “over-react” Transferred T cells won’t work if they

can’t bind their own HLA molecule



Dr A A Oyekunle

If there is a “match”, then why GvHD?

MHC antigens are the ones typically “matched”

There are several other “minor” tissue antigens other than the MHC e.g. H-Y

GvHD results from T cell reactivity toward polymorphisms between donor and hostThis can be good e.g. GvL, GvT

OR

This can be bad e.g. GvHD



Dr A A Oyekunle

Polymorphisms can help rid disease or cause GVHD H -Y

antigen from Y chromosome

expressed ubiquitously target for CTL

responses CTL response leads to

less relapse, more GVHD

HA-1 polymorphic unknown function expressed only on

hematopoietic cells target for CTL

responses CTL response leads to

less relapse, no GVHD Others: KIR antigens in multiple myeloma



Dr A A Oyekunle

Myeloablative SCTMyeloablative SCT

High dose High dose radiationradiation

High doseHigh dose chemochemo

Stem cellsStem cells

Watch and waitWatch and wait



Dr A A Oyekunle

Non-myeloablative SCT

ImmunoImmunosuppressionsuppression

Stem cellsStem cells

Manipulate the immune response Manipulate the immune response to maximize G vs. diseaseto maximize G vs. disease



Dr A A Oyekunle

Preventing GVHD• HLA matching• Best donor-recipient pair: age, CMV, gender,

parity, etc.• Rigorous infection screening and prophylaxis• Minimize tissue injury during conditioning• Specific GvH prophylaxis

• MRD myeloabl. SCT: Mtx + calcineurin inhibitor (CsA or tacrolimus)

• Others: T-cell depletion (in vitro, ex vivo, in vivo)• ATG, MMF, sirolimus, etc



Dr A A Oyekunle

GVHD Prophylaxis - How much?

Aggressive ProphylaxisAggressive Prophylaxis•LESS GVHDLESS GVHD•MORE infectionMORE infection•MORE relapseMORE relapse

Minimal ProphylaxisMinimal Prophylaxis•MORE GVHDMORE GVHD•LESS infectionLESS infection•LESS relapseLESS relapse

SURVIVALSURVIVAL



Dr A A Oyekunle

Treating GVHD

• 1st Line: Methylprednisolone alone

• MMF, tacrolimus, sirolimus• ATG• Oral non-absorbable steroids• Monoclonal antibodies• Pentostatin• Extracorporeal photopheresis• Mesenchymal stem cells

BENIN BLOOD & MARROW TRANSPLANT SOCIETY OF NIGERIA 15-27 JULY 2013. STEM CELL TRANSPLANT CENTRE,...

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