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To the Editor:

We read with interest the article by Rodriguez et al. in which an association between delayed-type-hypersensitivity (DTH)-regulation and HLA-DR matching was found (1). Our unpublished data, presented at ICTS 2002, looking at regulation by human CD4+CD25+ cells in vitro was consistent with their findings, but with an important caveat (Game and Lechler, abstract O239). We have hypothesised that CD4+CD25+ cells are self-HLA restricted and specific for a variety of self-antigens, although cross-reactivity with alloantigens will also occur (2). If this is the case then suppression of alloresponses is likely to be strongest in cases of HLA-DR matching.

We performed mixed lymphocyte reactions using cells purified from volunteers of known HLA-DR type. The responder populations were either whole CD4+ populations or CD4+CD25 cells—we predicted that the increase in cell proliferation or IL2 secretion upon depletion of CD4+CD25+ cells reflected the degree of suppression mediated by these cells. By dividing the result after depletion by the result before depletion, we calculated a ‘suppression ratio’. Indeed, the suppression ratio did follow the pattern 0 > 1 > 2 mismatches for HLA-DR as shown in Figure 1; the result for IL2 secretion was comparable (n = 8).

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Figure 1. The degree of suppression correlates with HLA-DR matching.

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However, closer analysis of the data raised an alternative possibility, which is difficult to rule out, namely, the degree of suppression is inversely correlated to the strength of the response. This is shown in Figure 2, which is accumulated data for the proliferation of CD4+ cells in the experiments described. Of note, Figure 1 by Rodriguez et al. appears consistent with this alternative.

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Figure 2. The increase in the MLR with HLA-DR mismatches.

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Rodriguez et al. did not explore the nature of the regulatory cells suppressing the DTH responses, but it seems reasonable to assume that all regulatory cells operate in a dose-dependent fashion. The concept that CD4+CD25+ cells suppress weaker reactions better than stronger reactions is not new (3) and must be taken into account when interpreting data on HLA-DR matching and regulation.

In either case, the data presented by Rodriguez et al. are consistent with the notion that regulatory cells, being self-HLA restricted and/or better at regulating weaker alloresponses, will regulate the indirect pathway of allorecognition more efficiently than the direct pathway (2,4).

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