1. 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

2. Graft versus Host Disease in HSCT BENIN BLOOD & MARROW TRANSPLANT SOCIETY OF NIGERIA 15-27 JULY 2013. STEM CELL TRANSPLANT CENTRE, BENIN 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.

3. Graft versus Host Disease in HSCT BENIN BLOOD & MARROW TRANSPLANT SOCIETY OF NIGERIA 15-27 JULY 2013. STEM CELL TRANSPLANT CENTRE, BENIN 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.

4. Graft versus Host Disease in HSCT BENIN BLOOD & MARROW TRANSPLANT SOCIETY OF NIGERIA 15-27 JULY 2013. STEM CELL TRANSPLANT CENTRE, BENIN Dr A A Oyekunle Auditors Dendritic cells B cells Macrophages Endothelial cells Kupffer cells Sample Outside Sample Inside Process Specimen Present Data

5. Graft versus Host Disease in HSCT BENIN BLOOD & MARROW TRANSPLANT SOCIETY OF NIGERIA 15-27 JULY 2013. STEM CELL TRANSPLANT CENTRE, BENIN 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 cell B cell Macrophage “Meaning of Life” “Trouble” signal

6. Graft versus Host Disease in HSCT BENIN BLOOD & MARROW TRANSPLANT SOCIETY OF NIGERIA 15-27 JULY 2013. STEM CELL TRANSPLANT CENTRE, BENIN Dr A A Oyekunle Pathogenesis of Acute GvHD Culled from Hematopoietic Stem Cell Transplantation; ESH-EBMT (2008).

7. Graft versus Host Disease in HSCT BENIN BLOOD & MARROW TRANSPLANT SOCIETY OF NIGERIA 15-27 JULY 2013. STEM CELL TRANSPLANT CENTRE, BENIN 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

8. Graft versus Host Disease in HSCT BENIN BLOOD & MARROW TRANSPLANT SOCIETY OF NIGERIA 15-27 JULY 2013. STEM CELL TRANSPLANT CENTRE, BENIN Dr A A Oyekunle Severity and Grading system (Glucksberg) Culled from Hematopoietic Stem Cell Transplantation; ESH-EBMT (2008).

9. Graft versus Host Disease in HSCT BENIN BLOOD & MARROW TRANSPLANT SOCIETY OF NIGERIA 15-27 JULY 2013. STEM CELL TRANSPLANT CENTRE, BENIN 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

10. Graft versus Host Disease in HSCT BENIN BLOOD & MARROW TRANSPLANT SOCIETY OF NIGERIA 15-27 JULY 2013. STEM CELL TRANSPLANT CENTRE, BENIN 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 host  This can be good e.g. GvL, GvT OR  This can be bad e.g. GvHD

11. Graft versus Host Disease in HSCT BENIN BLOOD & MARROW TRANSPLANT SOCIETY OF NIGERIA 15-27 JULY 2013. STEM CELL TRANSPLANT CENTRE, BENIN 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

12. Graft versus Host Disease in HSCT BENIN BLOOD & MARROW TRANSPLANT SOCIETY OF NIGERIA 15-27 JULY 2013. STEM CELL TRANSPLANT CENTRE, BENIN Dr A A Oyekunle Myeloablative SCT High dose radiation chemo chemo Stem cells Watch and wait

13. Graft versus Host Disease in HSCT BENIN BLOOD & MARROW TRANSPLANT SOCIETY OF NIGERIA 15-27 JULY 2013. STEM CELL TRANSPLANT CENTRE, BENIN Dr A A Oyekunle Non-myeloablative SCT Immunosuppression Stem cells Manipulate the immune response to maximize G vs. disease

14. Graft versus Host Disease in HSCT BENIN BLOOD & MARROW TRANSPLANT SOCIETY OF NIGERIA 15-27 JULY 2013. STEM CELL TRANSPLANT CENTRE, BENIN 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

15. Graft versus Host Disease in HSCT BENIN BLOOD & MARROW TRANSPLANT SOCIETY OF NIGERIA 15-27 JULY 2013. STEM CELL TRANSPLANT CENTRE, BENIN Dr A A Oyekunle GVHD Prophylaxis - How much? Aggressive Prophylaxis LESS GVHDLESS GVHD MORE infectionMORE infection MORE relapseMORE relapse Minimal Prophylaxis MORE GVHDMORE GVHD LESS infectionLESS infection LESS relapseLESS relapse SURVIVAL

16. Graft versus Host Disease in HSCT BENIN BLOOD & MARROW TRANSPLANT SOCIETY OF NIGERIA 15-27 JULY 2013. STEM CELL TRANSPLANT CENTRE, BENIN Dr A A Oyekunle Treating GVHD 1 st Line: Methylprednisolone alone MMF, tacrolimus, sirolimus ATG Oral non-absorbable steroids Monoclonal antibodies Pentostatin Extracorporeal photopheresis Mesenchymal stem cells