Immune reconstitution after allogeneic transplantation and expanding options for immunomodulation: an update

Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) has advanced to a common procedure for treating also older patients with malignancies and immunodeficiency disorders by redirecting the immune system. Unfortunately, cure is often hampered by relapse of the underlying disease, graft-versus-host disease, or severe opportunistic infections, which account for the majority of deaths after HSCT. Enhancing immune reconstitution is therefore an area of intensive research. An increasing variety of approaches has been explored preclinically and clinically: the application of cytokines, keratinocyte growth factor, growth hormone, cytotoxic lymphocytes, and mesenchymal stem cells or the blockade of sex hormones. New developments of allogeneic HSCT, for example, umbilical cord blood or haploidentical graft preparations leading to prolonged immunodeficiency, have further increased the need to improve immune reconstitution. Although a slow T-cell reconstitution is regarded as primarily responsible for deleterious infections with viruses and fungi, graft-versus-host disease, and relapse, the importance of innate immune cells for disease and infection control is currently being reevaluated. The groundwork has been prepared for the creation of individualized therapy partially based on genetic features of the underlying disease. We provide an update on selected issues of development in this fast evolving field; however, we do not claim completeness. (Blood. 2010; 115(19):3861-3868) IntroductionAllogeneic hematopoietic stem cell transplantation (HSCT) has become a common procedure for the therapy of hematologic malignancies and immune disorders. Donor bone marrow and mobilized peripheral blood stem cells are routinely used for the reconstitution of immune function in leukemia and lymphoma patients after radiation and/or chemotherapy. Recently, there have also been increasing attempts to treat solid tumors by immunotherapeutic approaches to induce a graft-versus-tumor effect, reviewed by Demirer et al. 1 Tempo of immune reconstitutionThe reconstitution of different immune cell subsets after an allogeneic HSCT occurs at different tempos. After the conditioning regimen there is the "aplastic phase" (neutropenia) until neutrophils recover at approximately 14 days after peripheral blood stem cell transplantation, approximately 21 days after bone marrow transplantation, and approximately 30 days after umbilical cord blood transplantation (UCBT). The infections encountered during the aplastic phase do not differ from those found in other neutropenic patients and consist primarily of bacterial infections. The first 100 days after HSCT are characterized by cellular immune deficiencies with a reduced number of cytotoxic lymphocytes, natural killer (NK) cells of the innate immune system, and T cells of the specific immune system (Figure 1). This renders the patient especially susceptible to viral and fungal infections. Rapid recovery of NK cells after HSCT is based on an expansion of the cytokine-producing CD56 bright NK-cell subset. ...

Depletion of naive T cells using clinical grade magnetic CD45RA beads: a new approach for GVHD prophylaxis

“…2,3 Therefore, CD45RA-depleted DLIs should accelerate the reconstitution of CD4 þ and CD8 þ T-cell immunity to pathogens, which might translate into lower infection-related morbidity and mortality after allogeneic hematopoietic SCT. 11 The use of CD45RA À memory T cells in adoptive immunotherapy could also circumvent the technically much more complex and pathogen-restricted ex vivo selection of pathogen-specific donor T cells by HLA-peptide multimers or cytokine secretion assays. 12,13 The absolute numbers of pathogen-reactive IFN-g spot-forming cells were overall not increased in CD45RA -memory T cells compared with original LPs.…”

Insufficient recovery of thymopoiesis predicts for opportunistic infections in allogeneic hematopoietic stem cell transplant recipients

“…24 Preservation of the thymic epithelium by new therapeutic approaches has, therefore, lately received more attention. [27][28][29] We evaluated thymic function by both the frequency of sjTREC + T cells and the sjTREC content per milliliter of peripheral blood. The latter estimate was added in order to correct for peripheral homeostatic T-cell expansion, which may result in dilution of sjTREC and subsequent underestimation of thymic function.…”

Knockdown of p21Cip1/Waf1 enhances proliferation, the expression of stemness markers, and osteogenic potential in human mesenchymal stem cells

“…They also appear promising for improving posttransplant immune reconstitution (Seggewiss & Einsele, 2010). Despite the variations in the isolation techniques, growth media, and culture conditions, which cause a remarkable difference in their proliferation and differentiation capacity (Pittenger, 2008), many studies have consistently reported MSCs, like other somatic cells, still undergo replicative senescence and lose proliferation and differentiation abilities upon serial passage in culture (Bonab et al, 2006;Shibata et al, 2007;Wagner et al, 2008).…”