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Hysterically Historical Histocompatibility or How do we Identify Deleterious Abs

Hysterically Historical Histocompatibility or How do we Identify Deleterious Abs. Ron Kerman, PhD Immune Evaluation Laboratory Baylor College of Medicine, Houston, Texas. Crossmatch. Rejection. No Rejection. Positive. 24. 6. Negative. 8. 187. Patel and Terasaki, NEJM 280:735, 1969.

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Hysterically Historical Histocompatibility or How do we Identify Deleterious Abs

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  1. Hysterically Historical HistocompatibilityorHow do we Identify Deleterious Abs Ron Kerman, PhD Immune Evaluation Laboratory Baylor College of Medicine, Houston, Texas

  2. Crossmatch Rejection No Rejection Positive 24 6 Negative 8 187 Patel and Terasaki, NEJM 280:735, 1969

  3. HLA antibodies are bad for transplant recipients. -Paul Terasaki Non-HLA antibodies may also be bad (anti-endothelial, vimentin, MICA, MICB and others).

  4. HLA antibodies instantly kill a kidney: hyperacute rejection State of preimmunization is detected by HLA antibodies HLA antibodies are associated with acute early rejection

  5. Hysterically Historical Histocompatibility Besides ABO confirmation, the crossmatch is the most important test performed in the Transplant Immunology Laboratory! The Crossmatch is King

  6. I might have been wrong! -Ron Kerman, 2014

  7. Graft Survival vs. Crossmatch 7

  8. Graft Survival vs. Crossmatch 8

  9. Graft Survival vs. Crossmatch 9

  10. Considerations in Delineating Clinically Relevant HLA Antibodies • Ab specificity • Ig type: IgG (1, 2, 3, 4), IgM, IgA • Complement fixing • Ab quantity: MFI, MESF, titer • Ab persistence

  11. New Bells and Whistles • We can now identify HLA Abs and their Ag specificities • We can identify donor-specific Abs • We can use MFIs to determine cut-offsfor unacceptable Ags • We can perform virtual crossmatches

  12. Is this what we want for our patients? There are problems with antibody binding to bead-antigen complexes There are problems with using MFI values to quantify Ab strength or concentration It follows that using MFIs for unacceptable Ags and virtual crossmatching may not be correct!

  13. Thoughts • All HLA or non-HLA Abs are not bad. • MFI values for DSAs may not be clinically informative. • Antibody titer , as a reflection of antibody strength (how much Ab is present) may be highly clinically informative.

  14. FI n Accumulative % 1,000 – 2,000 2,001 – 3,000 3,001 – 4,000 4,001 – 5,000 5,001 – 6,000 6,001 – 7,000 7,001 – 8,000 8,001 – 9,000 9,001 – 10,000 10,001 – 11,000 11,001 – 12,000 12,001 – 13,000 13,001 – 14,000 14,001 – 15,000 ≥19,001 - 6 2 12 6 10 2 4 - 4 6 1 2 1 2 2 10% 13% 33% 43% 60% 63% 70% - 77% 87% 88% 92% 93% 97% 100% • Fluorescence Intensity of Donor Specific Antigen Beads from Crossmatch (FCXM) Positive Sera (N=60) PRA ≥ 80%

  15. Elimination of unacceptable HLA antigens when present in transplant patient sera at neat, but not present at low titer. 39 high-PRA cI/cII sera evaluated for HLA Abs and their Ag specificities at neat and 1:16. cI cII PRA (%) 77 ± 25% 84 ±21% Number Ag specificities: • Neat 46 ±22 34 ±22 • 1:16 25 ± 12 19 ±13 Frequency of Ag Elimination (%) 75 ±25% 51 ±28%

  16. Recipient Specifications • 1:16 Dilution • A2, A68, B57, B73, • DR10, DR16 • DR4 • DQ DQ0603 NEAT-No Dilution A2, A68, A69, A80 B57, B58, B73, B76 CW15, CW5 DR0202, DR10, DR16 DR18, DR4, DR7 DQ0501, DQ0603 PRA CI = 100% / 81% N=18 • DSAs • A2 • B57 • DR10 • DR4 • DQ0501 • MFI • 9,300 • 11,100 • 4,200 • 8,600 • 3,350 • DSAs • A2 • B57 • DR10 • DR4 • DQ • MFI • 8,200 • 3,800

  17. HLA Ab, Specificity, Titer and FCXM HLA Ab FCXM 24 mo.GraftSurvival DS Non-DS Titer (+) (-) N 1. 15* + + 256 (+) 0% 2. 44 + + ≤16 (-) 91% 3. 10 + + ≤16 (+) 60% 2-yr GS of 91% for (-)vs60% for (+) FCXM P<0.01 17

  18. HLA Ab, Specificity, Titer and FCXM HLA Ab FCXM 12 mo.GraftSurvival DS Non-DS Titer (+) (-) N 2. 44 + + ≤16 (-) 91% 44/300 = 15% of total recipients(+) DSA , but a (-) FCXM44/54 ( 81.5% ) DSA (+) recips were XM (-) 18 A-A; 11 women; 6 Hispanic (25/44 = 57%)

  19. HLA Ab titer is important: • Patients with high titer donor-specific HLA Absmay be at risk for rejection and graft loss. • However, while patients with low titer donor-specific HLA Abs may be deemed virtual crossmatch positive, they may have true crossmatches that are negative and may be appropriate for transplantation with their donors.

  20. Thoughts • All HLA or non-HLA Abs are not bad. • MFI values for DSAs may not be clinically informative. • Antibody titer , as a reflection of antibody strength (how much Ab is present) may be highly clinically informative. • Titration / dilution studies of high-PRA, multiple antigen presenting sera, may allow for elimination of HLA Ab specificities present at neat, but not present at a low dilution.

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