Correspondence

Anticytomegalovirus T-Cell Clones

N Engl J Med 1996; 334:601February 29, 1996

Article

To the Editor:

The article by Walter et al. (Oct. 19 issue)1 provides important evidence that the infusion of donor–derived CD8+ cytotoxic T-cell clones specific for human cytomegalovirus proteins can promptly reconstitute cellular immunity against human cytomegalovirus in recipients of allogeneic bone marrow, thus reducing the risk of morbidity and mortality related to viral infection. However, we would like to comment on two points.

First, excretion of the virus in urine and its isolation from the throat have not been demonstrated to be predictive of cytomegalovirus disease in humans,2 and consequently these measures should not be used to monitor infection in the surveillance of marrow-graft recipients. Likewise, viremia does not necessarily precede nor is it associated with the development of cytomegalovirus disease in humans, and interstitial pneumonia in particular. Quantitation of antigenemia has been demonstrated to reflect more accurately the viral load, and such tests become positive days to weeks before viremia is detectable.3 We suggest that the use of adoptive immunotherapy could receive further support if sensitive methods of viral detection, such as an assay for antigenemia or quantitation of human cytomegalovirus DNA in blood by the polymerase chain reaction (PCR), were used (both techniques also have the capacity to reveal abortive infection due to human cytomegalovirus).3

Second, as stated by the authors, the persistence of transferred CD8+ cytotoxic cells was promoted by the recovery of the response of CD4+ human cytomegalovirus–specific helper T cells. The infusion of virus-specific polyclonal T-cell lines containing both CD4+ and CD8+ cells has been successfully used to control infection with the Epstein–Barr virus and related lymphoproliferative disorders of recipients of allogeneic bone marrow.4 The use of these cells, selected on the basis of their negligible reactivity to patient-derived cells, did not increase the occurrence of graft-versus-host disease. Therefore, considering that both the absence of cytotoxic T lymphocytes and the capacity of helper T cells to proliferate are correlated with a high risk of viral infection and interstitial pneumonia after bone marrow transplantation,5 we wonder whether the use of T-cell lines could result in more durable protection against human cytomegalovirus infection than does the use of T-cell clones.

Franco Locatelli, M.D.
Rita Maccario, B.Sc.
Giuseppe Gerna, M.D.
University of Pavia, 27100 Pavia, Italy

5 References

1. 1

   Walter EA, Greenberg PD, Gilbert MJ, et al. Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N Engl J Med 1995;333:1038-1044
   Full Text | Web of Science | Medline

2. 2

   Meyers JD, Ljungman P, Fisher LD. Cytomegalovirus excretion as a predictor of cytomegalovirus disease after marrow transplantation: importance of cytomegalovirus viremia. J Infect Dis 1990;162:373-380
   CrossRef | Web of Science | Medline

3. 3

   Gerna G, Furione M, Baldanti F, Percivalle E, Comoli P, Locatelli F. Quantitation of human cytomegalovirus DNA in bone marrow transplant recipients. Br J Haematol (in press).
   

4. 4

   Rooney CM, Smith CA, Ng CY, et al. Use of gene-modified virus-specific T lymphocytes to control Epstein-Barr-virus-related lymphoproliferation. Lancet 1995;345:9-13
   CrossRef | Web of Science | Medline

5. 5

   Ljungman P, Aschan J, Azinge JN, et al. Cytomegalovirus viraemia and specific T-helper cell responses as predictors of disease after allogeneic marrow transplantation. Br J Haematol 1993;83:118-124
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: We agree with Locatelli et al. that the assay for cytomegalovirus antigenemia1 and quantitation of cytomegalovirus DNA in blood by PCR2 are more sensitive methods than viral culture of urine, throat, and blood specimens for detecting the reactivation of cytomegalovirus in bone marrow–transplant recipients and may be useful for monitoring the antiviral effects of adoptive immunotherapy. Although these methods permit earlier detection of the reactivation of cytomegalovirus than conventional culture, the presence of viremia has the highest predictive value for cytomegalovirus disease.3 The antigenemia and PCR assays were not used to evaluate all the patients in our study because reports of the usefulness of these assays in bone marrow–transplant recipients had not been published at the time the study was initiated. However, blood samples obtained each week for the first 100 days after transplantation from the final six patients were evaluated for the presence of cytomegalovirus antigenemia and for cytomegalovirus DNA by PCR. All these samples were negative.

Locatelli et al. also suggest that donor-derived polyclonal T-cell lines enriched with cytomegalovirus-reactive T cells might be useful for the reconstitution of immunity. A disadvantage of administering T-cell lines that contain mixtures of CD4+ and CD8+ T cells is the difficulty of determining which subgroups contribute to the toxicity or efficacy of therapy. The bone marrow–transplant recipients treated with polyclonal T-cell lines containing cytotoxic T lymphocytes reactive to Epstein–Barr virus received the T-cell infusions 60 to 185 days after transplantation.4 Studies in animal models have demonstrated that the infusion of donor T cells late after marrow transplantation causes less graft-versus-host disease than T cells given soon after transplantation.5 Therefore, it may be premature to conclude that donor-derived T-cell lines will not cause graft-versus-host disease in human recipients if administered earlier after transplantation, when the risk of cytomegalovirus disease is highest.

Elizabeth A. Walter, M.D.
Philip D. Greenberg, M.D.
Stanley R. Riddell, M.D.
Fred Hutchinson Cancer Research Center, Seattle, WA 98104-2092

5 References

1. 1

   Boeckh M, Bowden RA, Goodrich JM, Pettinger M, Meyers JD. Cytomegalovirus antigen detection in peripheral blood leukocytes after allogeneic marrow transplantation. Blood 1992;80:1358-1364
   Web of Science | Medline

2. 2

   Einsele H, Ehninger G, Hebart H, et al. Polymerase chain reaction monitoring reduces the incidence of cytomegalovirus disease and the duration and side effects of antiviral therapy after bone marrow transplantation. Blood 1995;86:2815-2820
   Web of Science | Medline

3. 3

   Boeckh M, Bowden R. Cytomegalovirus infection in marrow transplantation. In: Buckner CD, ed. Technical and biological components of marrow transplantation. Boston: Kluwer Academic, 1995:97-136.
   

4. 4

   Rooney CM, Smith CA, Ng CY, et al. Use of gene-modified virus-specific T lymphocytes to control Epstein-Barr-virus-related lymphoproliferation. Lancet 1995;345:9-13
   CrossRef | Web of Science | Medline

5. 5

   Johnson BD, Truitt RL. Delayed infusion of immunocompetent donor cells after bone marrow transplantation breaks graft-host tolerance allows for persistent antileukemic reactivity without severe graft-versus-host disease. Blood 1995;85:3302-3312
   Web of Science | Medline