Immune reconstitution following autologous hematopoetic stem cell transplantation

Approximatively 10,000 autologous hematopoietic stem cell transplants are performed worldwide each year for a variety of malignant diseases (Horowitz, 1995). Randomized trial have shown that high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation can offer prolonged disease-free survival in solid tumors such as small cell carcinoma of the lung (Humblet et al., 1987) and breast carcinoma (Bezwoda et al., 1995), as well as in haematological malignancies such as non-Hogkin’s lymphoma in relapse, acute myelogenous leukemia and multiple myeloma (Bosly et al., 1992a; Philip et al., 1995; Zittoun et al., 1995; Attal et al., 1996).
Reconstitution of bone marrow following transplantation consist of two distinct phenomena: Numerical recovery of bone marrow cellular elements on the one hand, and functional return of a variety overlapping functions on the other.
Post-transplantation neutropenia and thrombocytopenia no longer represent major sources of morbidity: the use of myeloid growth factors (G-CSF and GM-CSF) has markedly accelerated neutrophil recovery of chemotherapy-induced neutropenia (Sheridan et al., 1989; Lazarus et al., 1991; Gisselbrecht et al, 1994; Symann et al., 1996), while the use of autologous mobilized peripheral blood stem cell (PBSC) has further shortened the duration of myelosuppression. Likewise, platelet transfusion and the promise of the clinical use of thrombopoietin will likely lead to a similar rapid platelet recovery.
While neutrophil and platelet reconstitution is frequently considered the endpoint of hematologic recovery following intensive chemotherapy and stem cell transplantation, this ignores the second arm of bone marrow recovery, that of functional reconstitution. In fact, lymphoid recovery occurs very slowly; Reconstitution of normal humoral and cellular immunity may take a year or more.
Immunologic abnormalities that persisting up to two years have also been observed following allogenic bone marrow transplantation (allo-BMT; Lum, 1987; Atkinson, 1990). Although there are similarities in immune reconstitution following allo-BMT unlike autologous transplantation involved acute of chronic graft-versus-host disease (GVHD) and the use of immunosuppressive therapy to control it. Both of these interfere in the early developmental stages of the recovering immune system. Autologous hematopoietic stem cell transplantation therefore appears to be the more straightforward model to study immune reconstitution following grafting.
a large body of literature on immune reconstitution following hematopoietic stem cell transplantation is devoted to allo-BMT. In constrast, relatively little is known about the delays in the immune reconstitution following autologous hematopoietic stem cell transplantation. Several hypothesis have been proposed to account for these delays in the immune reconstitution following autologous hematopoietic stem cell transplantation. Several hypotheses have been proposed to account for these delays: Terminal differentiation of T cells in the transplant recipient fails to proceed to its completion because of the absence of a normal thymic microenvironment because cells contained in the graft have been damaged by previous chemotherapy, or possibly because of immunosuppressive effects if some cytokines. To approach the problem of immune reconstitution, we began by investigating the functionality of T cells by posing the following questions; Exactly, what cellular functions are defective in T cells following autologous transplantation? Is signal transducation normal? If not, are all T cells uniformly defective or are only a fraction of them? Because of the known role played by cytokines in the empirical clinical immunotherapy of cancer, what is the production of cytokines in transplant recipients? Does the T cell content in the graft accelerate T cell reconstitution and T cell function transplantation?
To answer these questions, we used mitogens that activate T cells though different pathways in order to identify which of the pathways may be adversely affected. After confirming that the secretion of T cell-derived cytokines is frequently lower than normal following autologous transplantation, we then looked at T cell responsiveness to exogenously provided cytokines focusing primarily on IL-12 because of its known antitumoral effects. We found that NK and T cells do respond to exogenously IL-12 suggesting that this cytokine might prove useful in the transplantation setting. Post-transplantation immunodeficiency may be due not to the absence of a normally proliferative cytokine but to the overproduction of immunosuppressive one. For this reason, IL-10, a cytokine inhibiting the synthesis of IL-2, was studied and not found to be responsible for post-transplantation immunosuppression.
The study of mechanisms of immune restoration following high-dose chemotherapeutic conditioning regimens and autologous hematopoietic stem cell transplantation is not an academic one. Immediately following this therapeutically intensive approach, minimal tumor burden is presumed to be present, providing potentially ideal circumstances for immunotherapeutic intervention. Several strategies have been proposed. These have included new combinations of immunoregulatory cytokines and more recently the introduction of immunologically active genes. Toward this latter goal, we have proposed modifying the stem cell graft by introducing into transplanted cells genes encoding cytokines or a molecule involved in the co-stimulation pathway of T cell activation. Initial studies involved murine transplantation to evaluate the potential toxicity of increased gene expression.
in the first part of this discussion, we will focus on pathways of immune reconstitution of both V and T cells, primarily however on the functional recovery of T cell-mediated immunity. In the second part, we will discuss several strategies that could lead to enhancement of cellular immune function taking advantage of these particular circumstances of post-transplantation minimal residual disease. In the course of the discussion of these issues, we will describe our own contributions