Allogeneic haematopoietic stem cell donation and transplantation across the MHC class I barrier: "Faster is better than more. More is better than less".

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Citation

Heemskerk, M. B. A. (2006, September 28). Allogeneic haematopoietic stem cell donation and transplantation across the MHC class I barrier: "Faster is better than more. More is better than less". Retrieved from https://hdl.handle.net/1887/4578

Version: Corrected Publisher’s Version

License: Licence agreement concerning inclusion of doctoral thesis in the_{Institutional Repository of the University of Leiden} Downloaded from: https://hdl.handle.net/1887/4578

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6

Allogeneic MHC class I molecules with numerous

sequence differences do not elicit a CTL response.

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Abstract

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Introduction

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Materials and Methods

Donor/recipient pairs. 7KLVDQDO\VLVFRQFHUQHGGRQRUSDWLHQWSDLUVUHJLVWHUHGE\WKH(XURSGRQRUIRXQGDWLRQIURP WR7KHSDWLHQWVZHUHIURP'XWFKKDHPDWRSRLHWLFVWHPFHOOWUDQVSODQWDWLRQ FHQWHUV7KHGRQRUVRULJLQDWHGIURPWKHQDWLRQDOGRQRUUHJLVWU\RIWKH(XURSGRQRUIRXQGDWLRQ ,QWHUQDWLRQDOGRQRUUHJLVWULHVDQGUHODWHGGRQRUV$OOSDLUVKDGDVLQJOH+/$$%RU& DQWLJHQDOOHOHPLVPDWFKLQWKHJUDIWYHUVXVKRVWGLUHFWLRQDUHPLVPDWFKHGIRU+/$$ DQWLJHQPLVPDWFKHVDOOHOHPLVPDWFKHVIRU+/$%DQWLJHQPLVPDWFKDOOHOH PLVPDWFKHVDQGIRU+/$&DQWLJHQPLVPDWFKHVDOOHOHPLVPDWFKHV7KHVSHFL¿F +/$ DOOHOH PLVPDWFKHV RI DOO GRQRUUHFLSLHQW FRPELQDWLRQV WHVWHG DUH VKRZQ LQ7DEOH $OOSDLUVDUHFRPSDWLEOHIRUWKH+/$'5%DQG'4%DOOHOHV:HGLGQRWH[FOXGHWKH SDLUVZKLFKZHUH+/$'3%PLVPDWFKHGDVWKHSRZHURIWKHDQDO\VLVZRXOGEHFRPHWRR ORZ

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HLA-Cw*0303/HLA-Cw*0304 mismatched pairs.

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HLA genotyping and amino acid sequencing.

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Cytotoxic T-Lymphocyte precursor assay.

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Statistical analysis.

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Results

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Figure 1: Number of amino acid differences of single HLA class I incompatibilities versus T cell alloreactivity in vitro (CTLp/106 PBL). The

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Amino acid substitutions in the _ helices and ` sheet of MHC class I.

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Figure 2: Amino acid differences on positions 114 and 116 in the `sheet of MHC class I versus T cell alloreactivity in vitro (CTLp/106 PBL). The

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Figure 3: Number of amino acid differences in the _ helices of MHC class I versus T cell alloreactivity in vitro (CTLp/106_PBL)._{7KHQXPEHURISDLUVLQHDFKJURXSVLQJOH+/$$RU±%GLIIHUHQFHQ &7/S}

DQGQ &7/S!VLQJOH+/$&GLIIHUHQFHQ &7/SDQGQ &7/S!+RUL]RQWDO lines indicate the mean of each group. A statistical difference was found; HLA-C mismatched pairs with a undetectable CTLp frequency had on average a higher number of substitutions in the _ helices than the pairs with a detectable CTLp frequency (p = 0.03). No difference was found for HLA-A and -B differences (p = 0.67).

Figure 4: Number of amino acid differences in the ` sheet of MHC class I versus T cell alloreactivity in vitro (CTLp/106_PBL)._{7KHQXPEHURISDLUVLQHDFKJURXSVLQJOH+/$$RU±%GLIIHUHQFHQ &7/S}

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Table 2: Observed frequency of T cell mediated alloreactivity in vitro related to the number amino acid differences in the _ helices and in the ` sheet of single HLA-C differences. &7/SIUHTXHQF\) 1 &7/SIUHTXHQF\! *URXSA ₁ *URXSB A_{*URXSFRQWDLQVWKHSDLUVZLWK¿YHRUPRUHDPLQRDFLGGLIIHUHQFHVLQWKH_ helices} DQG¿YHRUPRUHLQWKH`VKHHWB_{*URXSLVWKHUHPDLQLQJJURXS*URXSKDVDQ} LQVLJQL¿FDQWQXPEHURIFDVHVZLWKDGHWHFWDEOH&7/SIUHTXHQF\FRPSDUHGWRJURXS ¿VKHU¶VH[DFWWHVWS

Figure 5: The number of amino acid differences in the _ helices and ` sheet of HLA-C versus T cell alloreactivity in vitro (HLA-CTLp/106_{PBL). The number of pairs in each}

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Discussion

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Figure 6: The number of amino acid differences in the _ helices and ` sheet of HLA-A or -B versus T cell alloreactivity in vitro (CTLp/106_{PBL). The}

number of pairs in each group: 12 within the group with an undetectable CTLp frequency and 23 within the group with detectable CTLp frequency. Please note

that certain pairs have similar numbers of amino acid differences on both _

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Figure 7: The possibility for TCR-MHC binding decreases if allogeneic MHC differs too much from autologous MHC. The peptide presented by the MHC

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References

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