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Identification of alloreactive T-cell epitopes on the Rhesus D protein

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Presentation on theme: "Identification of alloreactive T-cell epitopes on the Rhesus D protein"— Presentation transcript:

1 Identification of alloreactive T-cell epitopes on the Rhesus D protein
by Lisa-Marie Stott, Robert N. Barker, and Stanislaw J. Urbaniak Blood Volume 96(13): December 15, 2000 ©2000 by American Society of Hematology

2 PBMCs from all RhD-negative donors alloimmunized with RhD-positive RBCs proliferate in response to peptides from the sequence of the RhD protein.PBMCs were obtained from representative alloimmune donors 2 (A), 8 (B), and 13 (C) and tested for their ability ... PBMCs from all RhD-negative donors alloimmunized with RhD-positive RBCs proliferate in response to peptides from the sequence of the RhD protein.PBMCs were obtained from representative alloimmune donors 2 (A), 8 (B), and 13 (C) and tested for their ability to proliferate against the panel of peptides spanning the RhD protein. In each case, all the peptides were tested on a single occasion, and the broken line indicates the level of proliferation assumed to represent a positive response (the higher of SI = 3 or cpm = 1000). Lisa-Marie Stott et al. Blood 2000;96: ©2000 by American Society of Hematology

3 The pattern of RhD peptides that stimulate PBMCs from alloimmune donors to proliferate is reproducible.Proliferative responses of PBMCs from alloimmune donor 12 against the panel of peptides spanning the RhD protein were compared on 2 occasions (A and B) 2 ... The pattern of RhD peptides that stimulate PBMCs from alloimmune donors to proliferate is reproducible.Proliferative responses of PBMCs from alloimmune donor 12 against the panel of peptides spanning the RhD protein were compared on 2 occasions (A and B) 2 months apart. The broken line indicates the level of proliferation assumed to represent a positive response (the higher of SI = 3 or cpm = 1000). Lisa-Marie Stott et al. Blood 2000;96: ©2000 by American Society of Hematology

4 Variation in the number of RhD peptides that stimulate PBMCs from alloimmune donors to proliferate is strongly correlated with the level of anti-D antibody in their serum.Shown is the relation (Rs = 0.75; P < .003) between the number of RhD peptides that el... Variation in the number of RhD peptides that stimulate PBMCs from alloimmune donors to proliferate is strongly correlated with the level of anti-D antibody in their serum.Shown is the relation (Rs = 0.75; P < .003) between the number of RhD peptides that elicited proliferation of PBMCs from each of the deliberately alloimmunized donors (1-13) and the level of anti-D antibody in their serum. If antibody concentrations were measured more than once during the period in which PBMC samples were obtained, the highest level was recorded. Lisa-Marie Stott et al. Blood 2000;96: ©2000 by American Society of Hematology

5 PBMCs from control RhD-negative donors, who have not been alloimmunized, rarely proliferate when stimulated with peptides from the RhD protein sequence.Shown here are the proliferative responses of PBMCs from 3 control unimmunized RhD-negative donors (A, B,... PBMCs from control RhD-negative donors, who have not been alloimmunized, rarely proliferate when stimulated with peptides from the RhD protein sequence.Shown here are the proliferative responses of PBMCs from 3 control unimmunized RhD-negative donors (A, B, and C) against the panel of peptides spanning the RhD protein. The broken line indicates the level of proliferation assumed to represent a positive response (the higher of SI = 3 or cpm = 1000). Lisa-Marie Stott et al. Blood 2000;96: ©2000 by American Society of Hematology

6 The proliferation of PBMCs from alloimmune donors against RhD peptides is mediated by T cells.Shown are the proliferative responses of purified peripheral blood T cells from a representative alloimmune donor (22) against the smaller panel of peptides spanni... The proliferation of PBMCs from alloimmune donors against RhD peptides is mediated by T cells.Shown are the proliferative responses of purified peripheral blood T cells from a representative alloimmune donor (22) against the smaller panel of peptides spanning the RhD protein. The apparent discrepancy with the sequences that stimulated PBMCs from this donor (Table 2) was due to differences in the peptide panels screened and the greater responsiveness of the purified T cells. Thus, the T cells were not tested against 2 (17 and 28) of the 3 peptides (2, 17, and 28) that elicited proliferation of PBMCs from the same donor, and PBMCs did respond to 4 of the peptides (5, 8, 12, and 47) that stimulated the T cells, but the response was not strong enough to represent a significant difference. Lisa-Marie Stott et al. Blood 2000;96: ©2000 by American Society of Hematology

7 The proliferation of T cells from alloimmune donors against RhD peptides depends on HLA class II molecules.Cultures of PBMCs from a representative donor (6) were stimulated with RhD peptide, and class II–restricted responses were blocked by the addition of ... The proliferation of T cells from alloimmune donors against RhD peptides depends on HLA class II molecules.Cultures of PBMCs from a representative donor (6) were stimulated with RhD peptide, and class II–restricted responses were blocked by the addition of antibody specific for DP, DQ, DR, or DR15. ▪, no antigen; ■, RhD peptide 17. Lisa-Marie Stott et al. Blood 2000;96: ©2000 by American Society of Hematology

8 T cells from alloimmune donors that proliferate against RhD peptides in vitro were, with few exceptions, previously activated in vivo.Shown here are the proliferative responses of CD45RO+ (▪, previously activated) and CD45RA+ (■, previously inactive) T cell... T cells from alloimmune donors that proliferate against RhD peptides in vitro were, with few exceptions, previously activated in vivo.Shown here are the proliferative responses of CD45RO+ (▪, previously activated) and CD45RA+ (■, previously inactive) T cells from alloimmune donors 12 (A), 17 (B), and 4 (C,D) against selected RhD peptides. Lisa-Marie Stott et al. Blood 2000;96: ©2000 by American Society of Hematology

9 Particular peptides from the RhD protein stimulate T cells from most alloimmune donors to proliferate.Shown here is the proportion of alloimmune donors (n = 22; for peptides 34, 35, and 36, n = 5, since original results obtained using sequence Ile218 were o... Particular peptides from the RhD protein stimulate T cells from most alloimmune donors to proliferate.Shown here is the proportion of alloimmune donors (n = 22; for peptides 34, 35, and 36, n = 5, since original results obtained using sequence Ile218 were omitted) with T cells that proliferated in response to each of the 68 peptides from the panel spanning the RhD protein. Lisa-Marie Stott et al. Blood 2000;96: ©2000 by American Society of Hematology

10 RhD protein sequences that stimulate T cells from alloimmune donors to proliferate are not limited to extracellular loops.The predicted topographic features of the RhD protein5 6illustrate the location of the 4 dominant RhD peptides that elicited proliferat... RhD protein sequences that stimulate T cells from alloimmune donors to proliferate are not limited to extracellular loops.The predicted topographic features of the RhD protein5 6illustrate the location of the 4 dominant RhD peptides that elicited proliferation by T cells from most of the alloimmune donors. Residues within dominant peptides, ● (peptide 6 aa52-66, peptide 13 aa97-111, peptide 17 aa , and peptide 28 aa ). Lisa-Marie Stott et al. Blood 2000;96: ©2000 by American Society of Hematology

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