BONE MARROW TRANSPLANT

1. Transplantation
Immunology

2. Nobel Prize in Physiology or Medicine 1980
George D. Snell , Jean Dausset
■ HLA - MHC

3. HLA Basics
H = Human
L = Leukocyte
• White Cells
• Component of the immune system
• Recognizes self from non-self
A = Antigen – a substance that when introduced into the body
stimulates the production of an antibody.
HLA are the genes encoding for MHC

4. MHC: a cell receptor on antigen presenting
cells recognising the bodys self / nonself
HLA are the genes encoding for MHC
Proteins on the outer surfaces on most cells of the body
Inherited from our parents
Located on chromosome 6

6. 6 Different HLA Groups
Class
I
A B C
Class
II
DR DQ DP
Class I antigens: These antigens are found on the surface of all
nucleated cells in our body
Class II antigens: These antigens are found on B-cells and
macrophages

7. Each individual carries 10 to 12 genes that encode the HLA-A,
-B, -C, -DR, -DQ, and -DP. Most of these genes are highly
polymorphic, ranging from 13 (HLA-DRB4) to 699 (HLA-B)
alleles per locus
• A, B, DR important in related donors
• A, B, C, DR important in unrelated donors
• DQ, DP ???

8. group of alleles

9. DNA Based HLA Typing
Serologic : A01, B02, DR15
Low Resolution : A01XX, B02XX, DR15XX
Intermediate Resolution: Results are narrowed to 2 or more
alleles
A 01AB (0101, 0102)
B 02AC (0201, 0203)
DR 15MN (1503, 1505)
High Resolution: Identifies the specific allele
A 0102
B 0103
DR 1503

11. What is a Match?
Related Allogeneic BMTs:
6/6 A, B, DR high resolution match preferred
5/6 mismatch acceptable
Unrelated Allogeneic BMTs:
8/8 A, B, C , DR high resolution match preferred
7/8 mismatch acceptable
(Current practice prefers A mismatch, over B, over C, over
DR mismatches)
Cord Blood Transplants:
4/6 match or better

12. BMT- CTN recommendations

14. Effect of HLA on Clinical Outcomes after HSCT
Number of HLA Mismatches
• 10/10 allelic-matched unrelated donors (MUDs) = HLA-identical
sibling showed that overall survival, disease-free survival,
transplantation-related mortality (TRM), relapse, and acute GVHD
were not dependent on donor type.
• The similar outcome values for different donor types suggest that
well-selected UDs can perform as well as HLA-identical sibling
donors.

15. As the number of class I and II HLA mismatches increases,
the risks of graft failure, GVHD, and mortality increases.
 Each allele mismatch reduces overall survival at 1 year by
9% to 10%

17. HLA C
Mismatch C*03:03/C*03:04 is better tolerated and results in
superior outcomes compared with other single HLA
mismatches.
The apparent lack of effect of HLA-C allele level mismatch in the
study conducted by Lee and co-workers most likely resulted
from the predominance of this single, nonimmunogenic
mismatch.
Because other allele level mismatches at HLA-C may confer
higher risk for adverse outcomes, high resolution HLA-C
typing is warranted for evaluation of donor/recipient allele level
match grade.

18. The HLA loci A, B, C, and DRB1 are called high expression loci
(HEL), because their products are abundant on the cell surface and/or
mismatches are strongly associated with transplant outcome.
HLA-DRB3/4/5, -DQ, and -DP loci, whose products are expressed at
low levels, may be categorized as low expression loci (LEL)
Three or more mismatches at LEL were associated with poorer
overall survival and TRM in the 7/8 matched HEL group, and
therefore could be taken into account in donor selection when a
mismatched unrelated transplant is being considered

21. ETHNICITY- variations
• Morishima et al reported that the most frequent mismatch found in
Japanese patients was HLA-A*0201 and HLA-A*0206 and that this
mismatch was deleterious.
• By contrast, the most common HLA-A*02 mismatch in Caucasians
was found to be HLA-A*0201 and HLA-A*0205, and an adverse
relationship between this mismatch and transplantation outcomes was
not found.

22. HLA-DQ and HLA-DP
Conflicting data ?

24. Level of HLA Disparity
The level of HLA disparity (antigenic or allele level) affects
HSCT outcome differently
However, the NMDP study found that antigenic mismatch
was associated with higher mortality compared to allelic
mismatch

26. HLA Typing Is Based On Incomplete Information
-
Mutations in the membrane proximal, trans-membrane, and
cytosolic domains (limited sequencing)
Mutations in introns (not sequenced)
Mutations in promoter regions (not sequenced)
Mutations in alpha chains of class II proteins. DRA1, DQA1 and
DPA1 are not routinely sequenced for clinical typings
All clinical HLA typings are based on incomplete information. It
is possible that what we do not know could alter the expression of
an HLA allele

27. Donor (graft)
*
Recipient (host)
*
Match
category
†
(A, B,
C, DRB1)
Vector of
mismatch
Guideline for 7/8
matching
A
*
02:01, A
*
02:01 A
*
02:01, A
*
02:01 8/8 match
Homozygous Homozygous
A
*
02:01, A
*
03:01 A
*
02:01, A
*
02:01 7/8 mismatch HVG Less risk of
GVHD compared
with bidirectional
mismatch
Heterozygous Homozygous
A
*
02:01, A
*
02:01 A
*
02:01, A
*
03:01 7/8 mismatch GVH Same risks as
bidirectional
mismatchHomozygous Heterozygous
A
*
01:01, A
*
02:01 A
*
03:01, A
*
02:01 7/8 mismatch Bidirectional
(HVG and GVH)
Heterozygous Heterozygous
Table 1
Examples of HLA histocompatibility groups in study

28. Conclusion

29. `