Biomedical subjects

Stanley R Riddell

Publications and source records attributed to Stanley R Riddell.

36 records · Page 2Linked to original sources

PubMed2003

Induction of cytotoxic T-lymphocyte responses to enhanced green and yellow fluorescent proteins after myeloablative conditioning.

Lentiviral vectors are increasingly being used for transferring genes into hematopoietic stem cells (HSCs) due to their ability to transduce nondividing cells. Whereas results in in vitro studies and the nonobese diabetic/severe combined immunodeficiency (NOD/SCID) model have been highly encouraging, studies in large animals have not confirmed the superior transduction of HSCs using lentiviral vectors versus oncoretroviral vectors. In contrast to the stable gene marking we have consistently achieved with oncoretroviral vectors in animals that received myeloablative conditioning, we observed the complete disappearance of genetically modified enhanced green or yellow fluorescent protein-expressing cells in 5 baboons that received transplants of HSCs transduced with lentiviral vectors alone or in combination with oncoretroviral vectors. Immune responses to transgene products have been found to be involved in the disappearance of gene-modified cells after nonmyeloablative conditioning. Thus, we examined whether the disappearance of gene-modified cells after ablative conditioning may be due to an immune response. In 4 of 5 animals, cytotoxic T lymphocytes specific for the transgene protein were readily detected, demonstrating that immune reactions were responsible for the disappearance of the gene-marked cells in the animals. In summary, we report the induction of transgene-specific immune responses after transplantation of lentivirally transduced repopulating cells in a myeloablative setting.

Animals↗

PubMed2003

Female donors contribute to a selective graft-versus-leukemia effect in male recipients of HLA-matched, related hematopoietic stem cell transplants.

Male recipients of transplants from female (F-->M) hematopoietic stem cell donors represent a special group in whom donor T cells that are specific for recipient minor histocompatibility antigens encoded by Y-chromosome genes may contribute to a graft-versus-leukemia (GVL) effect and to graft-versus-host disease (GVHD). We examined the contribution of donor/patient sex to the risk for relapse and GVHD in 3238 patients who underwent HLA-identical sibling hematopoietic stem cell transplantation (HSCT) for hematopoietic malignancies at a single institution. Compared with other sex combinations, male recipients of female transplants had the lowest risk for relapse and the greatest odds for GVHD. Remarkably, after controlling for GVHD as a time-dependent covariate, F-->M HSCT still exhibited a lower risk for relapse than other sex combinations, demonstrating a selective GVL effect distinct from that contributed by GVHD. A reduction in relapse after F-->M HSCT was observed in patients with chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), and acute lymphoblastic leukemia (ALL). Taken together, these data suggest that minor H antigens encoded or regulated by genes on the Y chromosome contribute to a selective GVL effect against myeloid and lymphoid leukemias after F-->M HSCT.

Acute Disease↗

PubMed2003

Restoration of CD28 expression in CD28- CD8+ memory effector T cells reconstitutes antigen-induced IL-2 production.

The control of many persistent viral infections by Ag-specific cytolytic CD8+ T cells requires a concurrent virus-specific CD4+ Th cell response. This reflects in part a requirement of activated effector CD8+ T cells for paracrine IL-2 production as a growth and survival factor. In human CMV and HIV infection, the majority of differentiated virus-specific CD8+ T cells notably lose the ability to produce IL-2 but also lose expression of CD28, a costimulatory molecule. Analysis of the fraction of memory CD8+ T cells that continue to express CD28 revealed these cells retain the ability to produce IL-2. Therefore, we examined if IL-2 production by CD28- CD8+ T cells could be restored by introduction of a constitutively expressed CD28 gene. Expression of CD28 in CD28- CD8+ CMV- and HIV-specific CD8+ T cells reconstituted the ability to produce IL-2, which could sustain an autocrine proliferative response after Ag recognition. These results suggest that the loss of CD28 expression during differentiation of memory/effector CD8+ T cells represents a decisive step in establishing regulation of responding CD8+ T cells, increasing the dependence on CD4+ Th for proliferation after target recognition, and has implications for the treatment of viral disease with adoptively transferred CD8+ T cells.

CD28 Antigens↗

PubMed2003

Immune reconstitution to cytomegalovirus after allogeneic hematopoietic stem cell transplantation: impact of host factors, drug therapy, and subclinical reactivation.

Reconstitution of cellular immunity by 3 months after hematopoietic stem cell transplantation (HSCT) is a critical determinant of the long-term success of the transplantation. We analyzed the factors affecting recovery of cytomegalovirus (CMV)-specific CD4+ and CD8+ function at 3 months after HSCT by univariate and multivariable analyses including source of stem cells (bone marrow vs peripheral blood stem cells [PBSCs]), age, sex, graft-versus-host disease (GVHD), steroid use, conditioning regimens, ganciclovir use, HLA matching, circulating CMV antigenemia, absolute CD4+ and CD8+ counts, and donor CMV serology. High-dose steroids and CD4+ count less than 100 x 10(9)/L were significant predictors of impaired CD4+ functional recovery in the multivariable analysis. High-dose steroids, bone marrow as a source of stem cells, and CD8+ count less than 50 x 10(9)/L were associated with impaired CD8+ function in the multivariable analysis. Steroids were found to impair both CD4+ and CD8+ function in a dose-dependent manner. In the absence of high-dose steroids, low-level subclinical CMV antigenemia was found to stimulate both CD4+ and CD8+ functional recovery in recipients of ganciclovir prophylaxis. There was no difference in immune reconstitution between those who received prophylactic ganciclovir versus antigenemia-guided pre-emptive therapy. Thus, absolute CD4+ and CD8+ counts less than 100 x 10(9)/L and 50 x 10(9)/L, respectively; bone marrow as the source of stem cells; and high-dose steroid use all predict delayed recovery of functional T-cell immunity at 3 months after transplantation. Subclinical CMV reactivation while on ganciclovir appears to be a potent stimulator of T-cell function. These findings have implications for vaccination and adoptive-immunotherapy strategies in this population.

Adolescent↗

PubMed2003

A human minor histocompatibility antigen resulting from differential expression due to a gene deletion.

Minor histocompatibility antigens (minor H antigens) are targets of graft-versus-host disease and graft-versus-leukemia responses after allogeneic human leukocyte antigen identical hematopoietic stem cell transplantation. Only a few human minor H antigens have been molecularly characterized and in all cases, amino acid differences between homologous donor and recipient proteins due to nucleotide polymorphisms in the respective genes were responsible for immunogenicity. Here, we have used cDNA expression cloning to identify a novel human minor H antigen encoded by UGT2B17, an autosomal gene in the multigene UDP-glycosyltransferase 2 family that is selectively expressed in liver, intestine, and antigen-presenting cells. In contrast to previously defined human minor H antigens, UGT2B17 is immunogenic because of differential expression of the protein in donor and recipient cells as a consequence of a homozygous gene deletion in the donor. Deletion of individual members of large gene families is a common form of genetic variation in the population and our results provide the first evidence that differential protein expression as a consequence of gene deletion is a mechanism for generating minor H antigens in humans.

Animals↗

PubMed2003

Intracellular retention of the MHC class I-related chain B ligand of NKG2D by the human cytomegalovirus UL16 glycoprotein.

Infection by human CMV induces expression of the cellular MHC class I-related chain A (MICA) and chain B (MICB) surface proteins, which function as ligands for the activating NKG2D receptor. Engagement of NKG2D triggers NK cells and costimulates Ag-specific effector CD8 alphabeta T cells. The potency of MHC class I-related chain-NKG2D in stimulating these anti-viral immune responses may be countered by a CMV-encoded transmembrane glycoprotein, UL16, which specifically binds MICB as well as two of the UL16-binding proteins that are ligands of NKG2D. However, the function and significance of these interactions are undefined. Using a stably transfected B cell line, we show that expression of UL16 results in loss of surface MICB. This effect is caused by the failure of newly synthesized MICB to mature and transit the secretory pathway due to physical association with UL16. The intracellular retention of these protein complexes is mediated by a tyrosine-based motif in the cytoplasmic tail sequence of UL16, which determines localization to or retrieval from the trans-Golgi network. Deletion of this motif restores surface expression of MICB, whereas UL16 may be redirected to endosomal compartments. Predictably, the retention of MICB abrogates the stimulatory function of NKG2D. These results suggest a potential mechanism of viral immune evasion. However, this activity remains to be confirmed with CMV-infected fibroblasts or endothelial cells, in particular because MICB is normally coexpressed with MICA, which is not retained by UL16.

Amino Acid Sequence↗

PubMed2003

The graft versus leukemia response after allogeneic hematopoietic stem cell transplantation.

It is now well established that the efficacy of allogeneic hematopoietic stem cell transplant for eradicating a variety of hematologic malignancies is related to antitumor activity mediated by donor immune cells contained in the stem cell graft. Recent studies have provided fundamental insights into the nature of the effector cells and target molecules that are responsible for the graft versus tumor effect. T cells specific for minor histocompatibility antigens can mediate potent antitumor activity but are also responsible for graft versus host disease (GVHD). The molecular characterization of minor antigens has suggested ways of potentially separating antitumor activity from GVHD. The challenge for the future is to continue to build on our understanding of the allogeneic graft versus tumor effect and develop strategies that can be incorporated into clinical practice to augment this effect without GVHD.

Animals↗

PubMed2003

Disparity for a newly identified minor histocompatibility antigen, HA-8, correlates with acute graft-versus-host disease after haematopoietic stem cell transplantation from an HLA-identical sibling.

We recently identified a new minor histocompatibility antigen, termed HA-8, which is presented by human leucocyte antigen (HLA)-A*0201 or HLA-A*0202 and expressed ubiquitously among tissues. A retrospective analysis of 577 Caucasian patients with HLA-A*0201 or A*0202 who had received a haematopoietic stem cell transplant from a human leucocyte antigen (HLA)-identical sibling was conducted to determine whether HA-8 disparity correlated with clinical outcome. HA-8 disparity was detected in 72 recipients, and grades II-IV graft-versus-host disease (GVHD) occurred in 46 (64%), compared with 251 (50%) of the 503 patients without HA-8 disparity. After adjusting for known risk factors for acute GVHD, this difference was statistically significant (odds ratio, 1.8; 95% confidence interval, 1.0-3.1; P = 0.04). However, the hazards of clinical extensive chronic GVHD, overall mortality and recurrent malignancy were not statistically significantly different between the two groups. These data suggest that the increased risk of acute GVHD associated with recipient HA-8 disparity was not sufficient to change other clinical outcomes.

Acute Disease↗

PubMed2002

Targeted cloning of cytotoxic T cells specific for minor histocompatibility antigens restricted by HLA class I molecules of interest.

BACKGROUND: T cells specific for minor histocompatibility antigens (mHAgs) play a major role in both graft-versus-host disease and the graft-versus-tumor effect after HLA-identical bone marrow transplantation (BMT). However, characterization of individual T-cell responses to mHAgs is difficult and has generally involved extensive screening of T-cell clones isolated from bulk T-cell cultures generated from BMT recipients. In this report, we describe a new approach that permits both direct visualization of CD8 T-cell responses to mHAgs and cloning of T cells reacting with mHAgs presented by individual HLA alleles of interest. METHODS AND RESULTS: Panels of Epstein-Barr virus-transformed B-cell lines (B-LCL) expressing retrovirally transduced HLA cDNA were used as stimulator cells in an enzyme-linked immunospot (ELISPOT) assay to identify CD8 T cells reacting with mHAgs in cultures generated from postBMT recipient peripheral blood. T cells specific for mHAgs presented by selected HLA alleles could then be captured and cloned using an interferon-gamma secretion assay and magnetic bead selection. A majority of T-cell clones thus isolated exhibited cytolytic activity against the same HLA-transfected B-cell lines used for the ELISPOT assay. CONCLUSION: The ELISPOT assay was useful for identification of the HLA alleles presenting mHAgs recognized by individual T-cell lines. This approach for isolating mHAgs-specific CD8 T-cell clones should assist in characterizing responses restricted by HLA alleles of interest, which are common in a certain ethnic group.

Alleles↗

PubMed2002

Immunologic potential of donor lymphocytes expressing a suicide gene for early immune reconstitution after hematopoietic T-cell-depleted stem cell transplantation.

We have previously shown that the infusion of donor lymphocytes expressing the herpes simplex virus thymidine kinase (HSV-tk) gene is an efficient tool for controlling graft-versus-host disease (GVHD) while preserving the graft-versus-leukemia (GVL) effect. In addition to the GVL effect, the administration of donor HSV-tk(+) cells could have a clinical impact in promoting immune reconstitution after T-cell-depleted stem cell transplantation (SCT). To explore this hypothesis, we have investigated whether in vitro polyclonal activation, retroviral transduction, immunoselection, and expansion affect the immune competence of donor T cells. We have observed that, after appropriate in vitro manipulation, T cells specific for antigens relevant in the context of SCT are preserved in terms of frequency, expression of T-cell receptor, proliferation, cytokine secretion, and lytic activity. A reduction in the frequency of allospecific T-cell precursors is observed after prolonged T-cell culture, suggesting that cell manipulation protocols involving a short culture time and high transduction efficiency are needed. Finally, the long-term persistence of HSV-tk(+) cells was observed in a patient treated in the GVL clinical trial, and a reversion of the phenotype of HSV-tk(+) cells from CD45RO(+) to CD45RA(+) was documented more than 2 years after the infusion. Based on all this evidence, we propose a clinical study of preemptive infusions of donor HSV-tk(+) T cells after SCT from haploidentical donors to provide early immune reconstitution against infection and potential immune protection against disease recurrence.

Antigens, Viral↗

PubMed2002

Late cytomegalovirus disease and mortality in recipients of allogeneic hematopoietic stem cell transplants: importance of viral load and T-cell immunity.

Ganciclovir effectively prevents cytomegalovirus (CMV) disease in the first 100 days after allogeneic hematopoietic stem cell transplantation (HSCT), but late-onset CMV disease is increasingly observed. We designed a prospective cohort study to define the incidence and risk factors for late CMV infection in patients who undergo HSCT. CMV-seropositive patients were studied prospectively for CMV infection (quantitative pp65 antigenemia, quantitative CMV-DNA, blood culture), T-cell immunity (CMV-specific CD4(+) T-helper and CD8(+) cytotoxic T-lymphocyte responses, CD4 and CD8 T-cell count, absolute lymphocyte count), and other transplantation-related factors. Univariate and multivariable analyses were used to assess the risk for late CMV infection and disease and to assess overall survival. Late CMV disease developed in 26 of 146 (17.8%) patients a median of 169 days after transplantation (range, 96-784 days); the mortality rate was 46%. Thirty-eight percent of patients surviving late disease had a second episode a median of 79 days after the first episode. At 3 months after transplantation, preceding detection of CMV pp65 antigenemia, CD4 T-cell counts lower than 50 cells/mm(3), postengraftment absolute lymphopenia levels lower than 100 lymphocytes/mm(3), undetectable CMV-specific T-cell responses, and graft-versus-host disease (GVHD) were associated with late CMV disease or death. After 3 months, continued detection of pp65 antigenemia or CMV DNA in plasma or peripheral blood leukocytes and lymphopenia (fewer than 300 lymphocytes/mm(3)) were strong predictors of late CMV disease and death. In conclusion, CMV viral load, lymphopenia, and CMV-specific T-cell immunodeficiency are predictors of late CMV disease and death after allogeneic stem cell transplantation. Prevention strategies should be targeted at patients in whom CMV reactivated during the first 3 months and those with poor CMV-specific immunity or low CD4 counts.

Cytomegalovirus↗

PubMed2002

CD28 costimulation and immunoaffinity-based selection efficiently generate primary gene-modified T cells for adoptive immunotherapy.

The introduction of an inducible suicide gene has been proposed as a strategy to exploit the antitumor reactivity of donor T cells after allogeneic hematopoietic stem cell transplantation but permit control of graft-versus-host disease. However, there are several obstacles to this approach that may impair the ability of T cells to function and survive in vivo. These include the requirement for in vitro activation or long-term culture to introduce the transgene and obtain therapeutic cell numbers, the toxicity of drug selection to enrich transduced cells, and the immunogenicity of the transgene-encoded products. Here we have developed a transduction and selection strategy for generating large numbers of polyclonal T cells transduced with a retroviral vector encoding the human low-affinity nerve growth factor receptor (LNGFR) for selection and a Fas-based suicide construct (LV'VFas). Ligation of CD28 in conjunction with a T-cell receptor signal permitted efficient transduction, substantially promoted T-cell growth, and contributed to the generation of gene-modified T cells that retained clonal diversity, functional properties, and a homing receptor profile similar to untransduced peripheral blood lymphocytes. Microbeads conjugated directly to antibody specific to LNGFR significantly improved the immunomagnetic selection of LV'VFas-modified T cells and assisted in scaling of the selection procedure to therapeutic cell numbers. Thus, these studies identified a strategy that requires only a brief ex vivo culture and does not use drug selection to obtain large numbers of functional gene-modified polyclonal T cells that can be used for adoptive immunotherapy.

Animals↗

PubMed2002

Highly efficient gene transfer into baboon marrow repopulating cells using GALV-pseudotype oncoretroviral vectors produced by human packaging cells.

Vector-containing medium harvested from murine packaging cell lines has been shown to contain factors that can negatively influence the transduction and maintenance of hematopoietic stem cells. Thus, we generated a human packaging cell line with a gibbon ape leukemia virus pseudotype (Phoenix-GALV), and we evaluated vectors produced by Phoenix-GALV for their ability to transduce hematopoietic progenitor/stem cells. In 3 baboons, we used a competitive repopulation assay to directly compare GALV-pseudotype retrovirus vectors produced by either Phoenix-GALV or by the NIH 3T3-derived packaging cell line, PG13. In 3 additional baboons we compared Phoenix-GALV-derived vectors to more recently developed lentiviral vectors. Gene transfer efficiency into hematopoietic repopulating cells was assessed by evaluating the number of genetically modified peripheral blood and marrow cells using flow cytometry and real-time polymerase chain reaction. Transduction efficiency of hematopoietic repopulating cells was significantly higher using the Phoenix-GALV-derived vector as compared with the PG13-derived vectors or lentiviral vectors, with stable transduction levels up to 25%. We followed 2 animals for more than one year. Flow cytometric analysis of hematopoietic subpopulations in these animals revealed transgene expression in CD13(+) granulocytes, CD20(+) B lymphocytes, CD3(+) T lymphocytes, CD61(+) platelets, as well as red blood cells, indicating multilineage engraftment of cells transduced by Phoenix-GALV-pseudotype vectors. In addition, transduction of human CD34(+) cells was significantly more efficient than transduction of baboon CD34(+) cells, suggesting that Phoenix-GALV-derived oncoretroviral vectors may be even more efficient in human stem cell gene therapy applications.

Animals↗

PubMed2002

Association between immune recovery uveitis and a diverse intraocular cytomegalovirus-specific cytotoxic T cell response.

Cytomegalovirus (CMV) causes serious infection in individuals with deficient T cell immunity. In acquired immunodeficiency syndrome, the retina is a major site of progressive infection, despite the availability of therapy that targets CMV. The administration of highly active antiretroviral therapy to suppress human immunodeficiency virus frequently results in resolution of CMV retinitis, but this may be complicated by ocular inflammation termed "immune recovery uveitis" (IRU). To provide insight into the pathogenesis of IRU, the phenotype and specificity of intraocular T cells in a single patient were analyzed. The T cell infiltrate consisted of a diverse population of CD8(+) CMV-specific T cells, but only a minority of these T cells recognized the CMV phosphoprotein 65 and immediate early protein 1, which have been considered major targets of the host response. These results imply that reconstitution of CMV-specific T cells plays a role in IRU and suggest that the specificity of T cells engaged in the control of CMV at local sites of reactivation may be broad.

Cytomegalovirus↗

PubMed2002

HIV-1 Vpr does not inhibit CTL-mediated apoptosis of HIV-1 infected cells.

HIV-1 infected persons develop a robust CTL response to HIV antigens, yet HIV-1 is able to evade this host response and successfully replicate. The mechanism(s) of evasion is not completely defined but has been suggested to include resistance of infected cells to CTL-mediated apoptosis. The HIV-1 Vpr protein induces G2 arrest by indirectly inhibiting activation of cyclin B/p34cdc2 kinase. Granzyme B, the principle mediator of CTL-induced apoptosis, prematurely activates this same kinase complex. Therefore, we assessed the susceptibility of HIV-1 infected cells to CTL-mediated apoptosis to determine whether the expression of Vpr protected the infected cells from CTL-induced apoptosis. Antigen-specific CD8(+) CTL were able to induce apoptosis in HIV-1 infected cells and cells labeled with peptide corresponding to the CTL epitope with equivalent efficiency. This demonstrates that neither HIV-1 Vpr nor any other HIV protein directly inhibits CTL effector functions. Furthermore, we confirm that HIV-1 Nef is able to provide partial protection from CTL recognition of infected cells. Thus, the inability of CTL to control HIV-1 infection is likely not due to direct inhibition of CTL-mediated apoptosis.

Apoptosis↗

PubMed2002

Minor histocompatibility antigens--targets of graft versus leukemia responses.

Immune-mediated elimination of tumor cells by donor T cells recognizing recipient minor H antigens contributes to the curative potential of allogeneic HCT. The importance of the allogeneic response to a successful outcome is clearly illustrated by the results of stem cell transplant for malignancy after nonmyeloablative conditioning. Remarkably little is understood about the molecular nature of minor H antigens and this has impeded efforts to determine the role of specific disparities in graft versus tumor reactions or to manipulate T cell responses to augment antitumor activity without exacerbating GVHD. The isolation of minor H antigen-specific CD8+ and CD4+ T cell clones from recipients of allogeneic HCT has provided the reagents to characterize their expression on leukemic progenitors and to identify the genes encoding these antigens. Using cDNA expression cloning, genetic polymorphisms in the human IFI-75, Uty, KIAA0020, and UGT2B17 genes have been identified to encode new minor H antigens presented by HLA A3, B8, A2, and A29 respectively. Two of these genes are preferentially expressed in hematopoietic cells including leukemic progenitors suggesting it may be possible to augment T cell responses to promote a selective graft versus leukemia effect. A third gene, UGT2B17 is highly expressed in liver and GI tract and may be a target for GVHD in these organs. The studies to identify the molecular nature of minor H antigens have provided insights into the complexities of the graft versus host response associated with allogeneic HCT, but the challenge for the future will be to develop strategies that can selectively induce durable graft versus tumor effects without GVHD. A critical issue in developing specific immunotherapy to augment GVL responses is to determine which minor H antigens are expressed on leukemic stem cells. Studies using transplantation of human AML into SCID mice have identified a putative leukemic stem cell which is contained in the CD34+ CD38- subset of the blast population and is present in very low frequency (<1/200,000) in blood or bone marrow from AML patents. We have examined the ability of minor H antigen-specific CTL to prevent engraftment of human AML in NOD/SCID mice. These studies show that engraftment of leukemias derived from individuals encoding the minor H antigen can be specifically prevented demonstrating that AML stem cells express minor H antigens and are targets for CTL. One approach to determine directly which minor H antigens can be selectively targeted to induce a GVL effect without GVHD is to adoptively transfer T cell clones of defined specificity and function to patients who relapse after HCT. Studies of this approach are now in progress in acute leukemia and have provided important insights into potential obstacles of T cell therapy for relapsed leukemia after HCT.

Animals↗

PubMed2002

Expression of cutaneous lymphocyte-associated antigen by CD8(+) T cells specific for a skin-tropic virus.

Virus-specific CD8(+) T cells traffic to infected tissues to promote clearance of infection. We used herpes simplex virus type 2 (HSV-2) as a model system to investigate CD8(+) T cell trafficking to the skin in humans. Using human leukocyte antigen (HLA) class I tetramers, we observed that HSV-specific CD8(+) T cells in the peripheral blood expressed high levels of cutaneous lymphocyte-associated antigen (CLA). In contrast, CD8(+) T cells specific for non-skin-tropic herpesviruses lacked CLA expression. CLA-positive HSV-2-specific CD8(+) T cells had the characteristics of central memory cells, expressing CCR7, CD62L, and CD28, and they proliferated briskly in response to antigen. CLA is related to a functional E-selectin ligand, and both E-selectin and CLA-positive cells were detected in HSV-2-infected skin. HSV-2-specific T cells adhered to cells transfected with E-selectin. A higher proportion of HSV-specific CD8(+) T cells recovered from herpes lesions express CLA compared with blood, consistent with a role for CLA in skin homing. To our knowledge, this is the first report of expression of tissue-specific adhesion-associated molecules by virus-specific CD8(+) T cells. The evaluation of vaccines for skin and mucosal pathogens should include study of the induction of appropriate tissue-specific homing molecules.

Animals↗

PubMedDate not supplied

T-cell therapy of leukemia.

BACKGROUND: The demonstration that immune-mediated elimination of leukemia contributes to the success of allogeneic hematopoietic stem cell transplantation (HSCT) has renewed interest in the development of immune-based therapies that might be used to augment the antileukemic effect of HSCT or in patients who are not receiving HSCT. METHODS: The authors reviewed studies that have analyzed the mechanisms that may be operative in T-cell recognition of leukemia after allogeneic HSCT, identified candidate target antigens for immunotherapy of leukemia in transplant and nontransplant patients, and evaluated expression of candidate antigens on leukemic progenitors. RESULTS: A large number of potential targets for T-cell therapy or vaccination have now been identified in human leukemia. Studies to evaluate novel immune-based therapies are now being initiated. CONCLUSIONS: The rapid pace of progress in cellular and molecular immunology has identified new opportunities for developing T-cell therapy or vaccination for leukemia. Obstacles must be addressed before these approaches can be applied broadly, but the promising results of preclinical studies suggest continued efforts in this area will result in the establishment of immunotherapy as a useful modality in clinical practice.

Animals↗