Helper and cytotoxic T cell precursor frequencies are not predictive for development of acute graft-versus-host disease after partially T cell-depleted HLA-identical sibling BMT

Abstract

Summary:Despite the use of partially T cell-depleted grafts, 20% of the recipients of an HLA-identical sibling marrow graft develop aGVHD уII. This indicates that the current method for selecting a sibling donor, ie serological typing for HLA-A, B and DR, and a mixed lymphocyte culture (MLC) or molecular typing for HLA-DRB/DQB, is not predictive for aGVHD. In order to optimise our selection procedure, we retrospectively analysed patients who developed aGVHD уII by means of sequencing based typing for HLA-DPB and frequency analysis of alloreactive helper and cytotoxic T lymphocyte precursors (HTLp-f and CTLp-f). Patients who did not develop aGVHD or developed aGVHD grade I served as controls. Retrospective typing for HLA-DPB revealed only a single disparity in the group with aGVHD уII, indicating that mismatches for antigens other than HLA are the major cause of aGVHD in these patients. Furthermore, in our patient group, neither HTLp-f nor CTLp-f were predictive for development of aGVHD indicating that these assays in their current set-up are insufficiently sensitive to predict aGVHD in BMT with a partially T cell-depleted graft. We conclude, that HLA-identical siblings can be identified by means of serological typing for HLA-A and B and intermediate resolution molecular typing for DRB and DQB, but that for the prediction of aGVHD cellular tests with higher sensitivity and specificity as compared to the currently used HTLp-f and CTLp-f assays need to be developed. Keywords: bone marrow transplantation; HLA-identical sibling; cytotoxic T cell precursor frequency; helper T cell precursor frequency; HLA-DP Alloreactive T cells present in the allogeneic marrow graft are the initiators of acute graft-versus-host disease (aGVHD) after allogeneic bone marrow transplantation (BMT). Matching for human leukocyte antigens (HLA) is Correspondence: Dr A van der Meer, Transfusion Service, University Hospital Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands Received 9 May 1998; accepted 28 July 1998 therefore crucial to reduce the incidence of aGVHD. As the HLA gene cluster is inherited in a Mendelian fashion, HLA identity between patient and donor can be achieved by using sibling donors who have inherited the same HLA haplotypes. However, 20-40% of these patients still develop moderate to severe aGVHD. 1 It would obviously be a great achievement if this risk could be identified before transplantation, in order to either search for a more histocompatible (sibling) donor or alternatively, to intensify GVHD prophylaxis.The current procedures used for the identification of HLA-identical siblings are largely based on serological typing of HLA-A, B and DR, whereby class II identity is confirmed either by a mixed lymphocyte culture (MLC) or by molecular typing for HLA-DRB and DQB. This selection procedure does not take into account the following two aspects: firstly, although patient and sibling donor have inherited the same HLA haplotypes, it has become apparent that due to recombination, HLA-DP mismatches can be present in ...

Improved detection of clinically significant host-reactive antigens prior to HLA-identical sibling peripheral blood stem cell transplantation using a dendritic cell-based helper T-lymphocyte precursor assay

“…9,11,16,17 Although not all groups were able to confirm these findings. 7,10,12,13 Unfortunately, the statistical success of the HTLp assay has not translated into a routinely useful clinical assay.…”

“…Others have confirmed these results, 11 although some have not been able to confirm the ability of this assay to predict for acute GVHD. 10,12 This assay does not have the sensitivity to detect host-reactive antigenic differences between HLA-identical sibling donor/ recipient pairs.…”

“…[20][21][22][23] Previously, others and we have shown that the helper T-lymphocyte precursor (HTLp) assay can predict for the occurrence and severity of acute GVHD after bone marrow transplantation (BMT), although not all investigators have confirmed these results. [10][11][12][13][14][15][16][17][18][19] In contrast, more recently we have shown that the HTLp assay did not predict for GVHD in donor/recipient pairs undergoing peripheral blood stem cell transplantation (PBSCT). 24 Hence, the ability of the HTLp assay to predict for GVHD may depend on the source of the stem cells.…”

“…A variety of functional assays have been shown to be of variable ability in predicting GVHD. [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] More recently, cytokine gene polymorphisms have been shown to predict for some of the previously unexplained occurrence and severity of GVHD after stem cell transplantation. [20][21][22][23] Previously, others and we have shown that the helper T-lymphocyte precursor (HTLp) assay can predict for the occurrence and severity of acute GVHD after bone marrow transplantation (BMT), although not all investigators have confirmed these results.…”

The helper T lymphocyte precursor (HTLp) frequency does not predict outcome after HLA-identical sibling donor G-CSF-mobilised peripheral blood stem cell transplantation

“…Hence, assays are needed that can detect the presence of significant cryptic HLA or mHA, and that can assess the functional significance of any known HLA or mHA differences between the recipient and any particular donor. Over the years, several functional assays such as the MLR, 2 the mixed lymphocyte-epidermal cell reaction, 3 the skinexplant assay, 4,5 the cytotoxic T lymphocyte precursor (CTLp) assay [5][6][7][8][9][10][11] and the helper T lymphocyte precursor (HTLp) assay 5,[7][8][9][10][11][12][13][14][15][16][17] have been assessed by a number of investigators with mixed results.…”