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Graft-versus-host disease (GVHD) is a major complication associated with allogeneic bone marrow transplantation (BMT). Cyclosporin A (CsA) has been used as the basis for most immunosuppressive regimens for the prevention of GVHD, but has exhibited only limited effects and is hampered by nephrotoxicity, neurotoxicity, and hepatotoxicity. Previously, we showed that rD-mPGPtide, a structure-base designed peptide analog of the CDR3-like region of domain 1 of the murine CD4 molecule, suppressed the development of GVHD in a MHC-haploidentical murine BMT model when administered early in the course of disease. This peptide analog also inhibited T cell proliferation in mixed lymphocyte reactions (MLR) in vitro. The current results demonstrate that CsA and rD-mPGPtide exhibit an additive inhibitory effect on MLR. Furthermore, the use of CsA and rD-mPGPtide together for prevention of GVHD nearly doubled the median survival time of the mice compared to either agent alone. In addition, the combination therapy reduced the requirement for habitual administration of CsA. Therefore, the use of a CD4-CDR3 peptide can complement and potentiate the immunosuppressive effects of CsA in the prevention of GVHD following allogeneic BMT.

Protection from cytomegalovirus (CMV) disease in immunocompromised hosts has been shown to correlate with recovery of the host virus-specific CD8+ T-cell response. The administration of ganciclovir to immunosuppressed transplant recipients as antiviral prophylaxis has reduced the early risk of CMV disease, but late disease is observed with increased frequency, suggesting that recovery of the CMV-specific T-cell responses necessary for protective immunity may be delayed in these patients. Therefore, we evaluated reconstitution of CMV-specific T-cell responses in 47 bone marrow transplant (BMT) recipients entered on a randomized placebo-controlled study of ganciclovir. The study drug was initiated at a mean of 24 days after BMT. At day 30 to 40, a minority of patients had recovery of T-cell immunity to CMV and the frequency of reconstitution was equivalent in patients randomized to ganciclovir or placebo. The failure of ganciclovir to effect early reconstitution may reflect the short duration of treatment. Early recovery was associated with the infusion of BM from a CMV seropositive donor (P = .07 for CD8+ cytotoxic T cell (CTL), P = .04 for CD4+ Th). Between day 40 and day 90, recovery of deficient CD8+ and CD4+ CMV-specific T-cell responses occurred in the majority of individuals that received placebo, but in a minority of ganciclovir recipients. Two cases of late-onset CMV disease occurred in ganciclovir recipients. In all patients, the presence of a CTL response to CMV conferred protection from subsequent CMV disease (P = .005), and these protective CTL responses are shown to be specific for structural virion proteins similar to the responses in immunocompetent CMV seropositive individuals. These data confirm the importance of CMV-specific T-cell responses and suggest that a delay in recovery of these responses as a result of ganciclovir prophylaxis may contribute to the occurrence of late CMV disease.

The adoptive transfer of T cells specific for antigens encoded by pathogens and tumors has been an effective treatment for infections and malignancies in animal models and is potentially applicable for infections occurring in immunodeficient bone marrow transplant recipients. This article reviews recent insights derived from studies of the immunobiology of human cytomegalovirus (CMV) infection in healthy and immunodeficient hosts and the development of adoptive immunotherapy as prophylaxis for CMV infection in recipients of allogeneic bone marrow transplants.