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Immune Recovery Following Allogeneic Blood Transplantation

Mechanisms of Immune Dysfunction

  • Chapter
Allogeneic Stem Cell Transplantation

Part of the book series: Current Clinical Oncology ((CCO))

  • 94 Accesses

Abstract

High-dose chemotherapy (HDT) followed by stem cell transplantation (SCT), using mobilized blood stem cell product (BSCP), cord blood, or bone marrow (BM), is used to treat a variety of advanced malignancies, as well as congenital and autoimmune conditions. In the last decade, it has become apparent that following HDT with an SCT, using either an allogeneic or autologous BSCP, causes more rapid neutrophil, platelet, and immune recoveries to be observed in comparison to an SCT with a BM product. We and others have observed an immune dysfunction in the peripheral blood (PB) of patients following HDT and SCT despite restoration of total T cell numbers. This immunologic dysfunction includes an inversion in the CD4:CD8 T cell ratio and a depression of T cell function. Mechanistic studies have demonstrated a cell-mediated suppression of T cell function in mobilized BSCP and the PB of allogeneic and autologous SCT patients. This loss of function has been associated with increased T cell apoptosis, which occurs predominantly within CD4+ T cell subpopulations. The induction of apoptosis is mediated, at least in part, by Fas Ligand (FasL) expression on monocytes, which are found in significantly higher numbers in mobilized BSCP and in the PB following SCT. In addition, high levels of type 2 cytokines are found in the infused T cells and monocytes as well as in the PB post-transplantation. These defects in immune function may be clinically relevant, as the tolerance induced following HDT and SCT may limit the acute graft-vs-host disease (GVHD) that occurs following the infusion of 10- to 100-fold greater numbers of T cells by an allogeneic mobilized BSCP, as compared to bone marrow transplant trol. CD4+ and CD8+ T cells have been shown to have a pivotal role in controlling the initial infection and maintaining CMV and EBV in a latent state. EBV causes potentially lethal immunoblastic lymphomas in approx 25% of SCT recipients receiving a stem cell product from unrelated or HLA-mismatched donors. Risk factors, which include TCD, major MHCmismatched transplants, and intensity of immunosuppression, support the role of T cell immune surveillance in the control of EBV (188) and CMV infections. CMV pneumonitis (191), despite ganciclovir and specific immunoglobulin therapy, has a poor outcome with a mortality rate of 30–70% (192). Thus, strategies involving the adoptive transfer of CMV- or EBVspecific CTL clones or boosting of donor or patient immunity using CMV or EBV vaccines are encouraging. If the allo-donor is vaccinated, the T cells contained within the stem cell product include, in theory, viral-specific CTL. Alternatively, CTL may be derived following ex vivo-expansion of virus-specific CTL using donor leukocytes. In either case, the leukocytes or isolated T cells can be given either prophylactically or therapeutically for the treatment of CMV and EBV infections. The EBV-specific CTL are readily stimulated and expanded using EBV-immortalized B lymphoblastoid cell lines as stimulators. Current protocols for CMVspecific CTL use transfection of PP65, an immunodominant CMV antigen into CMV-infected fibroblasts, DCs or EBV-transformed B lymphoblastic cell lines and used for antigen stimulation (186). Thus, graft manipulation via antigen-specific T cell augmentation, either ex vivo or by donor vaccination, has significant potential as a strategy to affect infection. Further, the utilization of DLI from vaccinated donors or ex vivo-stimulated and expanded viral-specific CTLs provides an exciting new strategy for the control of these life-threatening viral infections (186). Regardless of the strategy used to prevent or treat infections, the marked and prolonged cellular immunodeficiency that is observed following SCT—especially following transplantation with positively selected stem cells—results in an increased incidence of infections, including rare and unusual infections, such as Pneumocystis carinii, toxoplasmosism and Mycobacterium species.

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  1. James E. Talmadge PhD
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  1. Allogeneic Transplant Program, Ireland Cancer Center, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, OH, USA

    Mary J. Laughlin MD

  2. Blood and Marrow Transplant Program, Ireland Cancer Center, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, OH, USA

    Hillard M. Lazarus MD

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Talmadge, J.E. (2003). Immune Recovery Following Allogeneic Blood Transplantation. In: Laughlin, M.J., Lazarus, H.M. (eds) Allogeneic Stem Cell Transplantation. Current Clinical Oncology. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-333-0_15

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