Regular ArticleProliferative and Cytotoxic Responses of Human Cord Blood T Lymphocytes Following Allogeneic Stimulation
Abstract
On the basis of the success of recent cord blood transplants, we undertook a comparison of the proliferative and cytotoxic potential, following allogeneic stimulation, of E-rosetted T cells from cord blood or adult peripheral blood (PB3) or bone marrow (BM). The magnitude of the proliferative response of cord blood (CB) T cells to alloantigen was greater than or equal to that of adult PB or BM T cells. Proliferation following culture with IL-2, IL-4, or IL-7 produced a similar result. In contrast, the cytotoxic activity in 10 20, or 30 mixed leukocyte culture of CB T cells was minimal, typically less than 20% at an effector:target ratio of 100:1. Cytometric analysis of CB T cell populations before and after culture with allostimulation demonstrated similar ratios of CD4+ and CD8+ cells in cultures of CB and adult T cells. Down-regulation of CD45RA antigen expression, a measure of CD4+ cell activation, was comparable in adult and CB cultures. Activation of CD8+ CTL effectors was assessed by the acquisition of CD28 antigen expression. After culture, a smaller proportion of CD8+CD28+ effector cells was present in CB cultures as compared to adult T cell cultures. Thus, following in vitro priming with alloantigen CB T cells generate a vigorous proliferative response yet produce little antigen-specific cytotoxicity. This diminished cytotoxicity may, in part, be related to the low incidence of graft vs host disease thus far noted in human CB transplants.
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Non-Graft-versus-Host Disease Enterocolitis Following Cord Blood Transplantation is Real, with Poorly Understood Pathophysiology, and Requires Distinct Management, with Eventual Resolution without Immune Suppression
2024, Transplantation and Cellular TherapyEnterocolitis is common after cord blood transplantation (CBT) and a specific, non-graft-versus-host disease (GVHD) entity with specific histopathologic features (“cord colitis”) has been described in some cases in selected series. Immune suppression is not without risk, and we have used it only when biopsy features are consistent with classical GVHD. In the absence of biopsy features of classical GVHD, our management of intestinal failure has been supportive, and we have withdrawn immune suppression to allow immune reconstitution and better prevent relapse of malignant disease and reduce infectious complications. We evaluated our approach over an 11-year period in a retrospective study of all patients at our large pediatric CBT center who experienced intestinal failure necessitating endoscopy and biopsy in the post-CBT period. We conducted a blinded histopathologic review of gastrointestinal (GI) biopsy specimens from all patients who had undergone GI endoscopy for intestinal failure in the post-CBT period. Patient records were evaluated to determine clinical HSCT course and outcome data, including mortality, relapse, and infection, as well as the duration of immune suppression and parenteral nutrition. Out of 144 patients who underwent CBT during the study period, 25 (17%) experienced intestinal failure requiring endoscopy. Thirteen patients were diagnosed with acute GVHD after blinded review of biopsy specimens, and 12 patients had non-GVHD enterocolitis. Management in the absence of GVHD on GI biopsy is supportive, with withdrawal of immune suppression in patients with malignant disease and continuing in accordance with institutional practice in those with nonmalignant disease. Compared with the GVHD cohort, the non-GVHD enterocolitis cohort had superior overall survival (91% versus 41%; P = .04) and a shorter duration of immune suppression (mean, 112 days versus 180 days; P = .049), reflecting these different management approaches. These results demonstrate that different histopathologic findings in those with intestinal failure after CBT likely indicates a different etiology from GVHD and mandates a different clinical management strategy to achieve optimal clinical outcomes.
Neonatal Immunity
2023, Principles of NeonatologyThe neonatal immune system matures rapidly after birth to acquire an ability to recognize and defend against potentially harmful pathogens, to tolerate and even promote commensal microbes, and to accept relatively harmless environmental antigens and dietary macromolecules. Although many components of the immune system perform nearly at par with adults, other branches are still maturing. The teleological significance of some of these alterations is still being elucidated. In this chapter, we describe the various arms of the neonatal immune system and compare these with their counterparts in adults.
Immunobiology of cord blood cells
2015, Cord Blood Stem Cells MedicineCord blood (CB) is a well-established source of stem cells for hematopoietic reconstitution that contains immune cells with a unique profile. This results in a balanced graft versus host alloreactivity allowing tolerance to human leukocyte antigen mismatch while maintaining a potent antitumor effect. CB immune cells are constitutively programmed to tolerate a wide range of nonself antigens presented both during pregnancy and early after birth during the intense period of bacterial colonization. Thus, there is a growing interest in characterizing better the properties of CB immune cells, in assessing the kinetics of immune reconstitution (IR) after CB transplantation (CBT), and in defining ex vivo strategies to induce fully competent cells for immunotherapy. Notably, this chapter aims to present up-to-date data on these topics. Published findings showed that CB cells are immature and produce less cytokines than their adult counterparts. The immaturity and naivety of CB cells could explain the lower Graft-versus-Host Disease (GvHD) risk after CBT but also raise some concerns about the quality of IR in CB transplanted patients. In this regard, recent data suggest that the use of appropriate conditioning regimes and GvHD prophylaxis, including the omission of T-cell depletion, can promote rapid expansion of naïve lymphocytes with a consequent restoration of the adaptive immunity early after transplantation. This evidence supports projects aiming to ex vivo generate fully competent immune cells for adaptive cellular immunotherapy. In conclusion, a better understanding of CB cell properties and of the environmental and epigenetic mechanisms involved during IR could help improving clinical outcomes and purposely designing cell therapy products derived from CB for use after CBT but also in broader clinical indications.
The role of the thymus in T-cell immune reconstitution after umbilical cord blood transplantation
2014, BloodUmbilical cord blood (UCB) is an alternative source of hematopoietic stem cells for patients without HLA-matched adult donors. UCB contains a low number of nucleated cells and mostly naive T cells, resulting in prolonged time to engraftment and lack of transferred T-cell memory. Although the first phase of T-cell reconstitution after UCB transplantation (UCBT) depends on peripheral expansion of transferred T cells, permanent T-cell reconstitution is mediated via a central mechanism, which depends on de novo production of naive T lymphocytes by the recipient’s thymus from donor-derived lymphoid-myeloid progenitors (LMPs). Thymopoiesis can be assessed by quantification of recent thymic emigrants, T-cell receptor excision circle levels, and T-cell receptor repertoire diversity. These assays are valuable tools for monitoring posttransplantation thymic recovery, but more importantly they have shown the significant prognostic value of thymic reconstitution for clinical outcomes after UCBT, including opportunistic infections, disease relapse, and overall survival. Strategies to improve thymic entry and differentiation of LMPs and to accelerate recovery of the thymic stromal microenvironment may improve thymic lymphopoiesis. Here, we discuss the mechanisms and clinical implications of thymic recovery and new approaches to improve reconstitution of the T-cell repertoire after UCBT.
Expanded umbilical cord blood T cells used as donor lymphocyte infusions after umbilical cord blood transplantation
2014, CytotherapyCitation Excerpt :The number of lymphocytes available is limited: the few millions of T cells present in 5% of the graft constitute the available material in the present study. Cord blood lymphocytes appear to be inefficient cytokine producers [33,34] and have reduced cytolytic activity [35]. The culture process alleviates some of these deficiencies: the number of cells attained is feasible for DLI use, and the cultured T cells have the capacity for cytokine production and re-activation to stimuli [16,18].
Umbilical cord blood (UCB) is an alternative graft source for hematopoietic stem cell transplantation and has been shown to give results comparable to transplantation with other stem cell sources. Donor lymphocyte infusion (DLI) is an effective treatment for relapsed malignancies after hematopoietic stem cell transplantation. However, DLI is not available after UCB transplantation.
In this study, in vitro–cultured T cells from the UCB graft were explored as an alternative to conventional DLI. The main aim was to study the safety of the cultured UCB T cells used as DLI because such cell preparations have not been used in this context previously. We also assessed potential benefits of the treatment.
The cultured UCB T cells (UCB DLI) were given to 4 patients with mixed chimerism (n = 2), minimal residual disease (n = 1) and graft failure (n = 1). No adverse reactions were seen at transfusion. Three of the patients did not show any signs of graft-versus-host disease (GVHD) after UCB DLI, but GVHD could not be excluded in the last patient. In the patient with minimal residual disease treated with UCB DLI, the malignant cell clone was detectable shortly before infusion but undetectable at treatment and for 3 months after infusion. In 1 patient with mixed chimerism, the percentage of recipient cells decreased in temporal association with UCB DLI treatment.
We saw no certain adverse effects of treatment with UCB DLI. Events that could indicate possible benefits were seen but with no certain causal association with the treatment.
A direct comparison of expression profiles of adhesion molecules on naïve T cells between cord blood and steady-state bone marrow grafts of healthy donors
2013, Transplantation ProceedingsWe compared the profiles of adhesion molecule expression on naïve T cells between umbilical cord blood (UCB) and steady-state bone marrow (SS-BM) grafts.
The expressions of 4 adhesion molecules, including very late antigen 4 (VLA-4), intercellular adhesion molecule-1 (ICAM-1), L-selectin, and lymophocyte function-associated antigen-1 (LFA-1) on naïve T cells in UCB (n = 25) and SS-BM (n = 10) were analyzed using flow cytometry.
The expressions of ICAM-1 and L-selectin on CD4+ T cells and CD8+ T cells in UCB were significantly lower than those on SS-BM (P < .05 for all). The expressions of VLA-4 and LFA-1 on CD8+ T cells in UCB were significantly lower than those of SS-BM (P = .002 and .047, respectively). Compared with SS-BM, we observed lower expression of ICAM-1 on naïve CD4+ and CD8+ T cells in UCB (P < .001 for all). The percentages of interferon (IFN)-γ positive cells among naïve CD4+ and CD8+ T-cell subsets were significantly lower in UCB, leading to ready polarization of naïve UCB T cells from a Th1 to Th2 phenotype versus those on SS-BM.
Our results among UCB suggested lower intensities of ICAM-1 expression on naïve T cells and their easier polarization from Th1 to Th2 elements.