Bad news for GVHD prevention

On the other hand, animals lacking all secondary lymphoid organs (SLOs) do not develop GVHD. This is bad news for programs testing the hypothesis that GVHD may be prevented or modulated by interfering with T-cell traffic. The study by Beilhack and coworkers shows that one needs to remove all peripheral lymphoid organs to achieve the goal of GVHD prevention, and this is not possible, nor desirable, in the clinical setting.

However, there is one intruiging finding in this study: blocking short-term homing ofT cells to SLOs with anti–MAdCAM-1 and anti–L-selectin monoclonal antibodies, plus splenectomy, totally prevented GVHD. This, unlike removal of all peripheral lymphoid organs, would be possible in the clinical setting.

The study raises several issues: in the first place, there is the anatomy of T-cell alloreactivity. The system must be set to be as efficient as possible, with the aim of protecting self from nonself, auto from allo. It is no surprise that T-cell priming can occur in any lymphoid organ, and removing only selected SLOs will not prevent alloreactivity. In order to prevent GVHD, one needs to remove all SLOs. The authors refer to this as redundancy: making sure T-cell priming does occur in the presence of alloantigens, wherever they are.

In the second place, there is the relationship between priming, T-cell migration, and tissue injury. It is not entirely clear why and how T cells are attracted to target organs. Is it the antigen-presenting cells (APCs) in those organs? Is it the antigens on the cell surface? The study by Beilhack and colleagues provides evidence that T-cell priming can occur in different SLOs, and once this happens, migration and injury to target organs will follow independently from the SLOs where T-cell priming has occurred.

In the third place, the study raises the following question: if it is so easy to induce GVHD in a mismatched model, then how is it that some patients can receive transplants from mismatched donors and still not develop GVHD? This is true not only for transplants from partially HLA-mismatched family donors (1-antigen–mismatched donors), but has been shown also for HLA-haplomismatched donor transplants. Rizzieri and coworkers have grafted high numbers of haplo-mismatched T cells with little resulting GVHD when using a conventional GVHD prophylaxis¹ . Similar results have been obtained by Huang et al.²  Therefore, T-cell alloreactivity can be modified with the use of antibodies and/or with growth factors to such an extent that GVHD is abrogated in some individuals. In keeping with these data, a prospective randomized study has shown reduction of acute and chronic GVHD in patients receiving T-cell antibodies before transplantation.³ 

In conclusion, there is more than one way to manipulate alloreactivity and pre-vent GVHD. Responsiveness of T cells can be down-regulated with T-cell antibodies, and T-cell priming within secondary lymphoid organs can be prevented with the use of specific antibodies and splenectomy. Whether we will be able to transfer results achieved in the animal model to our patients, and design improved transplantation protocols, remains to be determined in clinical trials.