Among the most common cause of transplant related mortality , approach and presentation simplified for PG students

1. DR AKSHAYA TOMAR
DEPT OF IMMUNOHEMATOLOGY AND BLOOD
TRANSFUSION
AFMC ,PUNE

2. 0.1 to 1% 1.2 to 6%

3. Why to know about GvHD?
 Delayed Engraftment
 Delayed Immune reconstitution
 Increased rate of infections
 Increased cost of treatment
 Increased length of hospital stay
 Adverse effects of chronic immunosuppressive therapy
 Increased morbidity and mortality

4. DIFFERENCE BETWEEN TA-GvHD & GvHD
 Unlike GVHD after allogeneic marrow transplantation,
TA-GVHD leads to profound marrow aplasia, with a
mortality rate higher than 90%.

5. INTRODUCTION
 Hematopoietic cell (marrow, umbilical cord blood or
mobilized peripheral blood) transplantation is performed
- To replace inadequate or defective blood cell production
- For adoptive immunotherapy in malignancy
- To reconstitute the immune system in immune deficiency
 The number of HSCTs has increased steadily over the past two
decades due to improvements in
- Outcome
- Expanded indications
- The ability to safely perform transplantation in
older individuals

6. INTRODUCTION
 Along with infection, GvHD is the leading cause of non-
relapse mortality following HSCT.
 Despite improvements in GvHD prevention,
approximately 30–60% of matched sibling HSCT
recipients will develop Acute GvHD (aGvHD) and the
rates are higher for unmatched or unrelated donors

7. ROLE OF HLA IN HSCT
 HLA system is generally viewed as second in importance only to
the ABO antigens in influencing the survival of transplanted
Bone marrow.
 In hematopoietic progenitor cell (HPC) transplantation, the HLA
system is paramount with regard to graft rejection and graft-vs-
host disease (GVHD)

8. ROLE OF HLA IN HSCT
 The role of HLA ‘compatibility’ falls into four different
areas:
1. Sufficient compatibility to permit engraftment and
prevent late rejection (with appropriate preparative
and immunosuppressive regimens)
2. Enough compatibility to minimize graft-versus-host-
disease (GVHD)
3. Ample immune reconstitution to permit
immunosurveillance
4. Sufficient immune potency to effect adoptive immune
therapy of neoplasia

10. GRAFT VS HOST DISEASE (GvHD)
 Complex immunological disorder caused by Donor T
Lymphocytes in allogenic HSCT
 GVHD results from the recognition of host tissues as
foreign by donor immunocompetent cells
 The incidence increases with greater HLA disparity
between the donor and host
 Fundamental problem for allogeneic transplantation is
the close association between this complication and
the derived benefit resulting from a GVT effect

11. GRAFT VS HOST DISEASE (GvHD)
 GvHD also delays the immune reconstitution in the recipient
 Reports of an increased incidence of chronic GvHD if more
than 8 × 106 CD34 cells/kg are transplanted suggest that
4–8 × 106 CD34 cells/kg should be regarded as the desirable
stem cell dose.
 PBSCs results in an increased incidence of chronic GvHD,
reflecting the five- to tenfold greater dose of T cells
transplanted if mobilized cells are used in preference to bone
marrow-harvested cells

12. RISK FACTORS
 Characteristics of Donor and Recipient
 HLA disparity
 Female donor (XX) to male donor (XY)
 Older age of recipient
 Prior history of aGvHD
 Characteristics of the transplantation protocol
 More intensive preparative regimen
 Source & dose of HSCT
 Unmodified (T cell replete) graft
 Less aggressive administration of prophylactic immunosuppressive
agents

13. RISK FACTORS
 Later Intervention
 Withdrawal of immunosuppressive medications
 Donor T Lymphocyte infusions
To Prevent/To treat
Relapse

14. REDUCED INTENSITY CONDITIONING
 Immunosuppress the host sufficiently to allow donor
engraftment, cure of disease being delivered
subsequently by the allogeneic GvL effect.
 Aim of the conditioning therapy is no longer principally
to eradicate disease

15. PATHOPHYSIOLOGY OF GvHD
GvHD
HLA
DISPARITY
IMMUNOCOMPETENT
GRAFT
IMMUNODEFICIENT
HOST

16. PATHOPHYSIOLOGY OF aGvHD

17. EXPANDED PATHOPHYSIOLOGY

18. Pathogenic
associated
molecular pattern

19. RISK OF GvHD IN REFERENCE TO SOURCE OF
STEM CELLS
PBSC
BONE
MARROW
UCB
IN ORDER OF DECREASING POTENTIAL

20. GRAFT VS TUMOR EFFECT (GVT)
 Most potent form of tumor immunotherapy currently in clinical
use
 Contribute towards curative aspect of allogenic HSCT
 Poorly understood
 Allogeneic T cells clearly play a fundamental role in the
initiation and maintenance of the effect on neoplastic cells
mainly CD8, CD4 and NK cells (Tumour specific CTLs)
 Beneficial effects seen in Leukemias , Myeloma and
Lymphomas

21. FORMS OF GvHD (Glucksberg-Seattle
classification)
ACUTE
(OCCURING
WITHIN 100 DAYS )
CHRONIC
(OCCURING AFTER
100 DAYS )
clinical manifestation and histologic findings are now the sole
factors used in defining these distinct entities

22. GRADING OF ACUTE GvHD

23. ACUTE GvHD
 Incidence is about 20-70%
 Depends upon
 Conditioning regimen intensity
 HLA disparity between donor and recipient
 Age of the recipient
 Stage of primary disease
 Clinical staging is established which takes into account
the primary organ involvement (Skin,Liver,GIT)
 Pathological findings do not change the grading

24. CUTANEOUS GVHD
Maculopapular
exanthema
perifollicular
papular lesions erythema
Purpura
Reticular
erythema

25. PROPHYLAXIS
 Steroids
 MTX
 Mycophenolate mofetil
 Cyclosporin/Tacrolimus (Calcineurin A Inhibitor)
 ATG
 Post transplant Cyclophosphamide
 T Cell Depletion Esp Cd45ra + T Cells
 α & β T Cell Depletion

26. There depletion
leads to less
severeGvHD
There excess leads to
more GvT

27. CHRONIC GvHD
 Reported in 60 to 70% of allogenic recipients
 Limited information available
 More extensive involvement but most people recover
 Involve practically all the organs
 Shares common features with many autoimmune
diseases like Scleroderma, Sicca syndrome etc

28. CHRONIC GvHD PATHOPHYSIOLOOGY
Decreased number of regulatory T cells
B cell dysregulation and production of autoantibodies
Decreased negative selection of T cells
Th2 type response Th2 Cytokines Increase
THYMIC DYSFUNCTION
Acute GvHD Conditioning

31. GVHD Prophylaxis - How much?
Aggressive Prophylaxis
•LESS GVHD
•MORE infection
•MORE relapse
Minimal Prophylaxis
•MORE GVHD
•LESS infection
•LESS relapse
SURVIVAL

32. RECENT ADVANCES
 ADOPTIVE IMMUNOTHERAPY
 EXTRACORPOREAL PHOTOPHERESIS
 MESENCHYMAL STEM CELLS

33. Adoptive
immunotherapy

35. REGULATORY T CELLS
 Regulatory T cells are characterized by the
 Co- expression of CD4,
 High levels of surface CD25,
 Master switch transcription factor called
forkhead box P3 (Foxp3) ; suppresses autoreactive lymphocytes
 Ultra lowdose IL-2 for GVHD prophylaxis after allo-HSCT
mediates expansion of Tregs without diminishing antiviral and
antileukemic activity
 Its still in clinical trial

36. CYTOTOXIC T CELLS
 Directed against minor histocompatibility antigens and tumor
associated antigens
 CD8+ cells
 By in vivo/ex vivo expansion, they can give enhanced GvT
without increasing the risk of GvHD
 CTL clones generation with IL21 exposure showed increased in
vivo life span with excellent tumor specific activity

37. CYTOKINE INDUCED KILLER CELLS (CIK)
 Cytotoxic effector T cells , CD3+ CD56+ TCR+
 Very strong non HLA restricted NK cell like cytotoxicity
 Completely lack GvHD activity
 Donor-derived CIK cells can be administered to
lymphoma/leukemia patients who relapsed after allo-HSCT
 Still in Phase I clinical trials

38. NK CELLS
 CD3- , CD56+ , CD16 + cells
 Rapidly kill certain target cells without prior immunization or
MHC restriction
 This cell type might prevent T cell–mediated GVHD through
killing
 Some tumor cells avoid recognition by CTL by down-regulating
their expression of MHC-I, but these escape mutants
consequently become targets for NK cells (No MHC needed for
presentation)

39. EXTRACORPOREAL PHOTOPHERESIS (ECP)
 ECP is a specialized procedure in which the buffy-coat layer is
collected from peripheral blood, treated with 8 methoxy-
psoralen and ultraviolet A light, and re-infused into the
patient.
 Cross-linking of leukocyte DNA, prevents replication and
induces apoptosis.
 ECP has complex immunomodulatory effects, including
induction of monocyte differentiation to dendritic cells,
alteration of T-cell subsets, and changes in cytokine
production profiles

40. ECP
INDUCED APOPTOSIS OF TREATED CELLS
REINFUSION
PHOTOACTIVATION
UV-A RADIATION
APHERESIS
MONONUCLEAR CELLS

41. Main effects of
ECP
Tolerogenic
dendritic cells
Anti-inflammatory
cytokine
production
Increased Treg
cells
ASFA recommends ECP for
Cutaneous manifestations
of GvHD as Category II
indication (does not
distinguish acute from
chronic)

42. MESENCHYMAL STEM CELLS
 Multipotent : can differentiate into osteocytes , fibroblasts ,
chondrocytes , myocytes and adipocytes
 They have inhibitory effects on the proliferation and cytotoxic
activity of immune system cells
 MSCs alter the cytokine secretion profiles of effector T cells,
DCs, and NK cells, shifting it from a pro-inflammatory Th1
cytokine profile to an anti-inflammatory Th2 cytokine profile
 Still in Phase III trials , have good results in Childhood
malignancies (Source of MSC : BM, HLA identical, Unrelated
donors)

43. Main effects of
MSC in GvHD
Suppresses DC
maturation and
activity
Anti-
inflammatory
cytokine
production
TGFβ,IL
10,PGE2,IL1R
Antagonist
Low CL I MHC
No CL II MHC
No Costimulatory
molecules

44. Ongoing Clinical Trials

45. SUMMARY
 Despite advances in procedure and post-transplantation
prophylaxis more than half of Allogenic HSCT patients develop
GvHD
 Major cause of morbidity and mortality
 Still poorly understood
 Elimination of alloreactive T cells and preserving tumor and
pathogen-specific immunity will still be a major task to further
improve outcome after HSCT

46. SUMMARY
 Unanswered questions remain:
 How to define the appropriate cell dose for optimal
therapeutic response and minimal toxicity?
 What is the best schedule to infuse these cells?
 Should these be infused as a preemptive or a curative
therapeutic dose?

47. Feb 2018;TRANSFUSION

48. BIBLIOGRAPHY
 Rossi’s principle of transfusion medicine 5th edition
 Mollison’s Blood Transfusion in clinical practice 12th edition
 AABB technical manual 18th edition
 Hoffbrand Postgraduate Hematology 5th edition
 Adoptive Immunotherapies After Allogeneic Hematopoietic
Stem Cell Transplantation in Patients With Hematologic
Malignancies – TRANSFUSION MEDICINE REVIEWS- 2015
 GVHD : comprehensive review – ANTICANCER RESEARCH 2017