Correspondence

Transplantation of Anergic Histoincompatible Bone Marrow Cells

N Engl J Med 1999; 341:1081-1082September 30, 1999

Article

To the Editor:

Guinan et al. (June 3 issue)1 reported an interesting method for preventing graft-versus-host disease after bone marrow transplantation. CTLA-4–Ig was added to a culture of a mixture of irradiated mononuclear cells from the recipient and marrow cells from the donor. After 36 hours, the recipient and donor cells were infused into the patient. The incidence of graft-versus-host disease after transplantation of haploidentical bone marrow (from a donor mismatched with the recipient for one HLA haplotype) was lower than expected. The authors attribute the inhibition of alloreactivity to anergy of the donor T cells, mediated by blockade of the B7:CD28 pathway.

In their study, however, high numbers of irradiated apoptotic recipient cells were injected, as indicated by the increase in the absolute number of CD3+ cells in the inoculum. Apoptotic cells induce the production of high levels of interleukin-10, which has immunosuppressive properties.2 Furthermore, antigen-presenting cells (of donor or recipient origin) may phagocytose an excess of apoptotic cells and present recipient antigens to donor T cells in a way that induces immune tolerance.3 To our knowledge, there are no studies of the use of recipient apoptotic cells to prevent graft-versus-host disease, but data recently obtained in our laboratory indicate that donor apoptotic cells can induce tolerance in the host. These results suggest that administration of ex vivo activated T cells or apoptotic cells, or both, with a bone marrow graft is not without immunologic consequences and could be an easy way to induce tolerance of host antigens.

Marcelo de Carvalho Bittencourt, M.D.
Pierre Tiberghien, M.D., Ph.D.
Philippe Saas, Ph.D.
Etablissement de Transfusion Sanguine de Franche Comté, 25020 Besançon CEDEX, France

3 References

1. 1

   Guinan EC, Boussiotis VA, Neuberg D, et al. Transplantation of anergic histoincompatible bone marrow allografts. N Engl J Med 1999;340:1704-1714
   Full Text | Web of Science | Medline

2. 2

   Gao Y, Herndon JM, Zhang H, Griffith TS, Ferguson TA. Antiinflammatory effects of CD95 ligand (FasL)-induced apoptosis. J Exp Med 1998;188:887-896
   CrossRef | Web of Science | Medline

3. 3

   Heath WR, Kurts C, Miller JFAP, Carbone FR. Cross-tolerance: a pathway for inducing tolerance to peripheral tissue antigens. J Exp Med 1998;187:1549-1553
   CrossRef | Web of Science | Medline

To the Editor:

We do not agree with Guinan et al. that their method reduces the need for immunosuppression after bone marrow transplantation. The recovery of T lymphocytes after transplantation was faster than expected, but Guinan et al. report that four patients died from infections (one of bacterial sepsis, two of aspergillus infection, and one of disseminated toxoplasmosis). The authors believe that these infections could be attributed to prolonged neutropenia, but neutropenia is not a risk factor for disseminated toxoplasmosis, which is associated with poor T-lymphocyte function.

Albi et al. have reported the presence of killer inhibitory receptors (KIR) on T cells after haploidentical transplantation.1 These receptors recognize particular groups of HLA antigens and thereby inhibit the immune response. KIR+ T cells lack CD28.2 This lack of CD28, together with the expression of KIR, could be responsible for the immunologic tolerance observed in the patients studied by Guinan et al. Moreover, KIR+ cytotoxic T lymphocytes are unable to control viral infections, which may explain the high rate of infections observed after haploidentical transplantation. Have Guinan et al. studied the expression of KIR on T cells in their system?

David Gallardo, M.D., Ph.D.
Albert Grañena, M.D., Ph.D.
Institut Català d'Oncologia

Joan García-López, M.D., Ph.D.
Cancer Research Institute, 08907 Barcelona, Spain

2 References

1. 1

   Albi N, Ruggeri F, Aversa F, et al. Natural killer (NK)-cell function and antileukemic activity of a large population of CD3+/CD8+ T cells expressing NK receptors for major histocompatibility complex class I after “three loci“ HLA-incompatible bone marrow transplantation. Blood 1996;87:3993-4000
   Web of Science | Medline

2. 2

   Mingari MC, Moretta A, Moretta L. Regulation of KIR expression in human T cells: a safety mechanism that may impair protective T-cell responses. Immunol Today 1998;19:153-157
   CrossRef | Medline

Citing Articles (2)

Citing Articles

1. 1

   Fran??ois Kleinclauss, Sylvain Perruche, Jean-Yves Cahn, Pierre Tiberghien, Philippe Saas. (2003) Administration of donor apoptotic cells: an alternative cell-based therapy to induce tolerance?1. Transplantation 75:Supplement, 43S-45S
   CrossRef

2. 2

   Philippe Saas, Pierre Tiberghien, Marcelo de Carvalho Bittencourt. (2002) Cell-based therapy approaches using dying cells: from tumour immunotherapy to transplantation tolerance induction. Expert Opinion on Biological Therapy 2:3, 249-263
   CrossRef