tretinoin and Graft-vs-Host-Disease

We encountered a 12-year-old girl with acute promyelocytic leukemia (APL) that occurred 21 months after a living donor partial orthotopic liver transplantation from her father for ornithine transcarbamylase deficiency. FK-506 had been administered for prophylaxis against graft-versus-host reaction. The bone marrow specimen revealed a massive infiltration of promyelocytic blasts (M3 by FAB classification) with chromosome 46, XX, t (15; 17) (q22; q12), being the recipient origin. A PML/RAR alpha chimeric gene was detected by RT-PCR. The patient was diagnosed as having APL and successfully induced to complete remission by chemotherapy including daunorubicin (DNR), cytarabine (araC), and all-trans retinoic acid (ATRA). She has been in continuous remission for 12 months after the treatment. Leukemia after liver transplantation is generally taken as a rare complication. However, recent advances in the survival rate of patients who have undergone liver transplantation will lead to an increase of such cases.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Cytarabine; Daunorubicin; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Leukemia, Promyelocytic, Acute; Liver Transplantation; Living Donors; Ornithine Carbamoyltransferase Deficiency Disease; Remission Induction; Tacrolimus; Tretinoin

B-cell receptor (BCR)-activated B cells contribute to pathogenesis in chronic graft-versus-host disease (cGVHD), a condition manifested by both B-cell autoreactivity and immune deficiency. We hypothesized that constitutive BCR activation precluded functional B-cell maturation in cGVHD. To address this, we examined BCR-NOTCH2 synergy because NOTCH has been shown to increase BCR responsiveness in normal mouse B cells. We conducted ex vivo activation and signaling assays of 30 primary samples from hematopoietic stem cell transplantation patients with and without cGVHD. Consistent with a molecular link between pathways, we found that BCR-NOTCH activation significantly increased the proximal BCR adapter protein BLNK. BCR-NOTCH activation also enabled persistent NOTCH2 surface expression, suggesting a positive feedback loop. Specific NOTCH2 blockade eliminated NOTCH-BCR activation and significantly altered NOTCH downstream targets and B-cell maturation/effector molecules. Examination of the molecular underpinnings of this "NOTCH2-BCR axis" in cGVHD revealed imbalanced expression of the transcription factors

Topics: Adaptor Proteins, Signal Transducing; Adult; Aged; Allografts; B-Lymphocytes; Chronic Disease; Female; Gene Expression Regulation, Neoplastic; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Interferon Regulatory Factors; Male; Middle Aged; Neoplasm Proteins; Receptor, Notch2; Receptors, Antigen, B-Cell; Signal Transduction; Tretinoin

CD8

Topics: Animals; CD8-Positive T-Lymphocytes; Cytokines; Disease Models, Animal; Forkhead Transcription Factors; Graft vs Host Disease; Humans; Mammals; Mice; Sirolimus; T-Lymphocytes, Regulatory; Tretinoin

Gastrointestinal (GI) graft-versus-host disease (GVHD) is a major barrier in allogeneic hematopoietic stem cell transplantation (allo-HSCT). The metabolite retinoic acid (RA) potentiates GI-GVHD in mice via alloreactive T cells expressing the RA receptor-α (RARα), but the role of RA-responsive cells in human GI-GVHD remains undefined. Therefore, we used conventional and novel sequential immunostaining and flow cytometry to scrutinize RA-responsive T cells in tissues and blood of patients who had received allo-HSCT and to characterize the impact of RA on human T-cell alloresponses. Expression of RARα by human mononuclear cells was increased after exposure to RA. RARαhi mononuclear cells were increased in GI-GVHD tissue, contained more cellular RA-binding proteins, localized with tissue damage, and correlated with GVHD severity and mortality. By using a targeted candidate protein approach, we predicted the phenotype of RA-responsive T cells in the context of increased microenvironmental interleukin-23 (IL-23). Sequential immunostaining confirmed the presence of a population of RARαhi CD8 T cells with the predicted phenotype that coexpressed the effector T-cell transcription factor T-bet and the IL-23-specific receptor (IL-23R). These cells were increased in GI- but not skin-GVHD tissues and were also selectively expanded in the blood of patients with GI-GVHD. Finally, functional approaches demonstrated that RA predominantly increased alloreactive GI-tropic RARαhi CD8 effector T cells, including cells with the phenotype identified in vivo. IL-23-rich conditions potentiated this effect by selectively increasing β7 integrin expression on CD8 effector T cells and reducing CD4 T cells with a regulatory cell phenotype. In summary, we have identified a population of RA-responsive effector T cells with a distinctive phenotype that is selectively expanded in human GI-GVHD and that represents a potential new therapeutic target.

Topics: Aged; CD8-Positive T-Lymphocytes; Cell Division; Cells, Cultured; Coculture Techniques; Female; Gastrointestinal Diseases; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Interleukin-23; Lymphocyte Count; Male; Middle Aged; Receptors, Interleukin; Retinoic Acid Receptor alpha; T-Box Domain Proteins; Tretinoin; Young Adult

Topics: CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Graft vs Host Disease; Humans; Interleukin-23; Tretinoin

Intestinal graft-versus-host disease (GVHD) remains a devastating complication after allogeneic hematopoietic stem cell transplantation (HSCT). Although it has been well established that gut-tropic donor T cells expressing integrin α4β7 are required to cause intestinal damage, the factors that control the induction of this pathogenic T cell population remain to be identified. Retinoic acid (RA) plays an important role in inducing α4β7 expression on T cells. In this study, we showed that gene expression of retinaldehyde dehydrogenase, the key enzyme involved in RA biosynthesis, is significantly increased in the spleen and mesenteric lymph nodes (MLNs) of irradiated mice. In a C57BL/6-into-B6D2F1 allogeneic HSCT model, irradiation significantly increased the induction of α4β7

Topics: Aldehyde Dehydrogenase 1 Family; Animals; Dendritic Cells; Gastrointestinal Microbiome; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Retinal Dehydrogenase; Signal Transduction; T-Lymphocytes; Transplantation, Homologous; Tretinoin; Whole-Body Irradiation

Recent studies have underscored the critical role of retinoic acid (RA) in the development of lineage-committed CD4 and CD8 T cells in vivo. We have shown that under acute graft-versus-host disease (GVHD) inflammatory conditions, RA is upregulated in the intestine and is proinflammatory, as GVHD lethality was attenuated when donor allogeneic T cells selectively expressed a dominant negative RA receptor α that blunted RA signaling. RA can function in an autocrine and paracrine fashion, and as such, the host cell lineage responsible for the production of RA metabolism and the specific RA-metabolizing enzymes that potentiate GVHD severity are unknown. In this study, we demonstrate that enhancing RA degradation in the host and to a lesser extent donor hematopoietic cells by overexpressing the RA-catabolizing enzyme CYP26A1 reduced GVHD. RA production is facilitated by retinaldehyde isoform-2 (RALDH2) preferentially expressed in dendritic cells (DCs). Conditionally deleted RA-synthesizing enzyme RALDH2 in host or to a lesser extent donor DCs reduced GVHD lethality. Improved survival in recipients with RALDH2-deleted DCs was associated with increased T cell death, impaired T effector function, increased regulatory T cell frequency, and augmented coinhibitory molecule expression on donor CD4

Topics: Aldehyde Oxidoreductases; Animals; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Dendritic Cells; Female; Gene Expression Regulation, Enzymologic; Graft vs Host Disease; Mice; Mice, Inbred BALB C; Mice, Transgenic; Retinoic Acid 4-Hydroxylase; Tretinoin

Adoptively transferred regulatory T-cells represent a promising therapeutic approach for tolerance induction in autoimmunity and transplantation medicine. However, a major hurdle for clinical application is the manufacturing of sufficient Treg cell numbers with respect to the low frequency of naturally occurring Tregs in the peripheral blood. Therefore, ex vivo large-scale expansion is mandatory for most of the clinical conditions. Besides the Treg cell number other parameters of the cell product are of high relevance for safe and efficient clinical Treg cell application like Treg cell purity, suppressive capacity and genetic stability of the Treg cell phenotype. Moreover, migratory properties of ex vivo expanded Tregs should be defined very clearly in order to predict their migration to secondary lymphoid organs as sites of antigen-specific activation, in vivo proliferation and subsequent trafficking to affected target organs. Therefore, we studied different cell culture conditions for Treg large-cell expansion using all-trans retinoic acid (ATRA) and/or rapamycin (Rapa) with focus on their migratory properties. The tested culture conditions revealed comparable chemokine receptor expression profiles (CXCR3, CCR4, CCR6, CCR7) and functional migration capabilities (IP10 and CCL19) with respect to Th1 and Th2 inflammatory conditions. However, the most striking difference was detected for the expansion capacity, suppressive potency and genetic stability likely predisposing large-scale expansion with ATRA and/or Rapa for therapeutic intervention in acute GvHD and without supplementation for chronic GvHD.

Topics: Acute Disease; Cell Culture Techniques; Cell Movement; Cell Proliferation; Cells, Cultured; Chronic Disease; Graft vs Host Disease; Humans; Immune Tolerance; Immunotherapy, Adoptive; Receptors, Chemokine; Sirolimus; T-Lymphocytes, Regulatory; Th1 Cells; Th1-Th2 Balance; Th2 Cells; Transcriptome; Tretinoin

Antigen-specific regulatory T cells (Tregs) possess the potential to reduce excess immune responses in autoimmune diseases, allergy, rejection after organ transplantation and graft-versus-host disease (GVHD) following hematopoietic stem cell transplantation. Although in vitro-expanded antigen-specific induced Tregs (iTregs) have been considered to be a promising therapeutic agent against such excessive immune reactions, the instability of iTregs after transfer is a fundamental problem in their clinical application. In this study, we searched for the optimal way to generate stable iTregs for the prevention of the murine GVHD model, in which conventional iTregs are reported to be inefficient. Allo-antigen-specific iTregs were generated by co-culturing naive T cells with allogenic dendritic cells in the presence of TGF-β and retinoic acid. By examining various agents and genes, we found that vitamin C stabilized Foxp3 expression most effectively in adoptively transferred iTregs under a GVHD environment. Vitamin C treatment caused active DNA demethylation specifically on the conserved non-coding sequence 2 (CNS2) enhancer of the Foxp3 gene locus in allo-antigen-specific iTregs and reduced iTreg conversion into pathogenic exFoxp3 cells. Vitamin C-treated iTregs suppressed GVHD symptoms more efficiently than untreated iTregs. Vitamin C also facilitated induction of a FOXP3high iTreg population from human naive T cells, which was very stable even in the presence of IL-6 in vitro. The treatment of vitamin C for iTreg promises innovative clinical application for adoptive Treg immunotherapy.

Topics: Animals; Ascorbic Acid; Disease Models, Animal; Graft vs Host Disease; Humans; Immunotherapy, Adoptive; Isoantigens; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; T-Lymphocytes, Regulatory; Tretinoin

Regulatory T cells (Tregs) suppress other immune cells and are critical mediators of peripheral tolerance. Therapeutic manipulation of Tregs is subject to numerous clinical investigations including trials for adoptive Treg transfer. Since the number of naturally occurring Tregs (nTregs) is minute, it is highly desirable to develop a complementary approach of inducing Tregs (iTregs) from naïve T cells. Mouse studies exemplify the importance of peripherally induced Tregs as well as the applicability of iTreg transfer in different disease models. Yet, procedures to generate iTregs are currently controversial, particularly for human cells. Here we therefore comprehensively compare different established and define novel protocols of human iTreg generation using TGF-β in combination with other compounds. We found that human iTregs expressed several Treg signature molecules, such as Foxp3, CTLA-4 and EOS, while exhibiting low expression of the cytokines Interferon-γ, IL-10 and IL-17. Importantly, we identified a novel combination of TGF-β, retinoic acid and rapamycin as a robust protocol to induce human iTregs with superior suppressive activity in vitro compared to currently established induction protocols. However, iTregs generated by these protocols did not stably retain Foxp3 expression and did not suppress in vivo in a humanized graft-versus-host-disease mouse model, highlighting the need for further research to attain stable, suppressive iTregs. These results advance our understanding of the conditions enabling human iTreg generation and may have important implications for the development of adoptive transfer strategies targeting autoimmune and inflammatory diseases.

Topics: Animals; Butyrates; Female; Forkhead Transcription Factors; Graft vs Host Disease; Humans; Interferon-gamma; Interleukin-10; Interleukin-17; Interleukin-2; Lymphocyte Activation; Methylation; Mice, Inbred NOD; Sirolimus; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Tretinoin

Topics: Allografts; Animals; CD4 Antigens; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Mice; Receptors, Retinoic Acid; T-Lymphocytes; Tissue Donors; Tretinoin; Vitamin A Deficiency

Graft-versus-host disease (GVHD) is an intractable complication in transplant patients. Regulatory T cells (Tregs) have the ability to prevent GVHD and consist of two subsets: natural Tregs (nTregs) and induced Tregs (iTregs). In comparison to nTregs, iTregs originate in the periphery under certain conditions and show improved proliferative and suppressive abilities in an inflammatory milieu. All-trans retinoic acid (atRA) favors Treg expansion and FoxP3 expression in human Tregs. However, whether atRA can affect the function of iTregs from transplant patients remains inconclusive. Therefore, we sorted naïve T cells from liver transplant patients and cultured them in vitro. Further analyses were performed to assess the suppressive function of iTregs in vitro and in vivo. atRA favored expansion and forkhead box P3 expression in iTregs from transplant patients. In comparison to iTregs from healthy donors, iTregs from transplant patients showed decent suppressive abilities in vitro and in vivo. Our findings suggest that atRA can potentially improve the development and function of iTregs from transplant patients. Furthermore, our results provide novel insights into Treg therapy in GVHD clinical trials.

Topics: Adolescent; Adult; Animals; Cell Differentiation; Cell Transplantation; Cytokines; Female; Forkhead Transcription Factors; Graft vs Host Disease; Humans; Liver Transplantation; Male; Mice, Transgenic; Middle Aged; T-Lymphocytes, Regulatory; Tretinoin; Young Adult

All-trans retinoic acid (atRA), the active derivative of vitamin A, has been shown to regulate Treg and T effector cell differentiation. However, the potential use of atRA as a treatment for acute graft-verse-host disease (aGVHD) has not been realized. Here we studied the ability of atRA to prevent and treat acute-GVHD in the B6-to-F1(D2B6F1) murine model. Our results showed that atRA consistently displayed a potent ability to control aGVHD development and reduce mortality by suppressing the expansion of donor T cells and inhibiting cytokine expression from donor CD8 cells. Interestingly, CD4(+)Foxp3(+) regulatory T cells were markedly increased in the spleens of atRA-treated mice. In vitro treatment with atRA inhibited T cell proliferation in a dose-dependent manner. Injection of an anti-IL-2 antibody impaired the protection by atRA in aGVHD. Therefore, these results strongly implicate atRA as a novel therapeutic strategy for controlling aGVHD progression and treating other inflammatory diseases.

Topics: Animals; Cytokines; Graft vs Host Disease; Mice, Inbred C57BL; Mice, Inbred DBA; Signal Transduction; Spleen; T-Lymphocytes, Regulatory; Tretinoin

Damage to the gastrointestinal tract during graft-versus-host disease (GVHD) is one of the major causes of morbidity and mortality in allogeneic hematopoietic stem cell transplant (HSCT) recipients. In the current study, we identified a critical role for the retinoic acid (RA) signaling pathway in the induction and propagation of gastrointestinal GVHD. The administration of exogenous RA significantly increased expression of the gut-homing molecules, CCR9 and α4β7, on donor T cells in mesenteric lymph nodes, and augmented the accumulation of proinflammatory CD4(+) and CD8(+) T cells within the gut mucosa, leading to a selective exacerbation of colonic GVHD and increased overall mortality. Conversely, depletion of RA in recipient mice by vitamin A deprivation resulted in a dramatic reduction of gut-homing molecule expression on donor T cells after HSCT. Significantly, absence of the RA receptor-α on donor T cells markedly attenuated the ability of these cells to cause lethal GVHD. This observation was attributable to a significant reduction in pathological damage within the colon. These findings identify an organ-specific role for RA in GVHD and provide evidence that blockade of the RA signaling pathway may represent a novel strategy for mitigating the severity of colonic GVHD.

Topics: Animals; Bone Marrow Transplantation; Cells, Cultured; Colon; Gastrointestinal Diseases; Graft vs Host Disease; Lymphoma; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Organ Specificity; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Severity of Illness Index; Signal Transduction; Tretinoin

Graft-versus-host disease (GVHD) is a critical complication after allogeneic bone marrow transplantation. During GVHD, donor T cells are activated by host antigen-presenting cells and differentiate into T-effector cells (Teffs) that migrate to GVHD target organs. However, local environmental factors influencing Teff differentiation and migration are largely unknown. Vitamin A metabolism within the intestine produces retinoic acid, which contributes to intestinal homeostasis and tolerance induction. Here, we show that the expression and function of vitamin A-metabolizing enzymes were increased in the intestine and mesenteric lymph nodes in mice with active GVHD. Moreover, transgenic donor T cells expressing a retinoic acid receptor (RAR) response element luciferase reporter responded to increased vitamin A metabolites in GVHD-affected organs. Increasing RAR signaling accelerated GVHD lethality, whereas donor T cells expressing a dominant-negative RARα (dnRARα) showed markedly diminished lethality. The dnRARα transgenic T cells showed reduced Th1 differentiation and α4β7 and CCR9 expression associated with poor intestinal migration, low GVHD pathology, and reduced intestinal permeability, primarily via CD4(+) T cells. The inhibition of RAR signaling augmented donor-induced Treg generation and expansion in vivo, while preserving graft-versus-leukemia effects. Together, these results suggested that reagents blunting donor T-cell RAR signaling may possess therapeutic anti-GVHD properties.

Topics: Animals; Bone Marrow Transplantation; Cell Differentiation; Graft vs Host Disease; Intestines; Mice; Receptors, Lymphocyte Homing; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Signal Transduction; T-Lymphocytes; T-Lymphocytes, Regulatory; Th1 Cells; Tretinoin

The transfer of alloreactive regulatory T (aTreg) cells into transplant recipients represents an attractive treatment option to improve long-term graft acceptance. We recently described a protocol for the generation of aTreg cells in mice using a nondepleting anti-CD4 antibody (aCD4). Here, we investigated whether adding TGF-β and retinoic acid (RA) or rapamycin (Rapa) can further improve aTreg-cell generation and function. Murine CD4(+) T cells were cultured with allogeneic B cells in the presence of aCD4 alone, aCD4+TGF-β+RA or aCD4+Rapa. Addition of TGF-β+RA or Rapa resulted in an increase of CD25(+)Foxp3(+)-expressing T cells. Expression of CD40L and production of IFN-γ and IL-17 was abolished in aCD4+TGF-β+RA aTreg cells. Additionally, aCD4+TGF-β+RA aTreg cells showed the highest level of Helios and Neuropilin-1 co-expression. Although CD25(+)Foxp3(+) cells from all culture conditions displayed complete demethylation of the Treg-specific demethylated region, aCD4+TGF-β+RA Treg cells showed the most stable Foxp3 expression upon restimulation. Consequently, aCD4+TGF-β+RA aTreg cells suppressed effector T-cell differentiation more effectively in comparison to aTreg cells harvested from all other cultures, and furthermore inhibited acute graft versus host disease and especially skin transplant rejection. Thus, addition of TGF-β+RA seems to be superior over Rapa in stabilising the phenotype and functional capacity of aTreg cells.

Topics: Acute Disease; Allografts; Animals; Antibiotics, Antineoplastic; Antibodies, Monoclonal, Murine-Derived; B-Lymphocytes; CD4 Antigens; CD40 Ligand; Cell Differentiation; Cells, Cultured; Coculture Techniques; Forkhead Transcription Factors; Gene Expression Regulation; Graft vs Host Disease; Interleukin-2 Receptor alpha Subunit; Mice; Mice, Inbred BALB C; Mice, Knockout; Sirolimus; Skin Transplantation; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Tretinoin

Graft versus host disease (GVHD) is the major complication of allogeneic bone marrow transplantation (BMT) and limits the therapeutic efficacy of this modality. Although the role of natural T-regulatory cells (nTreg) in attenuating GVHD has been extensively examined, the ability of induced T-regulatory cells (iTreg) to mitigate GVHD is unknown. The purpose of this study was to examine the ability of in vitro and in vivo iTregs to abrogate GVHD.. We examined the ability of in vitro differentiated and in vivo iTregs to reduce the severity of GVHD in a clinically relevant mouse model of BMT. The effect of blockade of interleukin (IL) 6 signaling on the efficacy of these Treg populations was also studied.. In vitro differentiated iTregs fail to protect mice from lethal GVHD even when administered at high Treg:effector T-cell ratios. Lack of GVHD protection was associated with loss of Foxp3 expression and in vivo reversion of these cells to a proinflammatory phenotype characterized by secretion of IFN-γ. Phenotypic reversion could not be abrogated by blockade of IL-6 signaling or by in vitro exposure of iTregs to all-trans retinoic acid. In contrast, the in vivo induction of iTregs was significantly augmented by IL-6 blockade and this resulted in reduced GVHD.. Instability of Foxp3 expression limits the utility of adoptively transferred iTregs as a source of cellular therapy for the abrogation of GVHD. Blockade of IL-6 signaling augments the ability of in vivo iTregs to prevent GVHD but has no effect on in vitro differentiated iTregs.

Topics: Animals; Antibodies, Blocking; Bone Marrow Transplantation; Forkhead Transcription Factors; Gene Expression Regulation; Graft vs Host Disease; Immunologic Factors; Inflammation; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Phenotype; Receptors, Interleukin-6; Signal Transduction; T-Lymphocytes, Regulatory; Tretinoin

Organ transplant recipients are generally considered to be at greater risk for developing malignant disorders because of prolonged immunosuppression for organ grafting, but acute leukemia is a rare complication after organ transplantation (0.2 -2.5%). We encountered two girls with acute promyelocytic leukemia (APL) after living donor partial orthotopic liver transplantation. In one patient, APL developed 21 months after liver transplantation for ornithine transcarbamylase deficiency. She had been administered tacrolimus for prophylaxis of graft-versus-host reaction. In the other patient, APL was diagnosed 46 months after liver transplantation for congenital biliary atresia. Both patients were successfully treated by chemotherapy including all-trans retinoic acid (ATRA), and after reaching complete remission, they have subsequently been in continuous remission. Although leukemia after liver transplantation is generally thought of as a rare complication, increases in survival rate following liver transplantation is likely to lead to more such cases, and documentation of these cases is therefore of importance.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biliary Atresia; Child; Child, Preschool; Cytarabine; Daunorubicin; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Leukemia, Promyelocytic, Acute; Liver Transplantation; Living Donors; Ornithine Carbamoyltransferase Deficiency Disease; Remission Induction; Tacrolimus; Tretinoin

Topics: Acute Disease; Adult; Dermatologic Agents; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Keratosis; Leukemia, Myeloid; Nipples; Treatment Outcome; Tretinoin

To explore the effect of all-trans retinoic acid (RA) on the engraftment of unrelated umbilical cord blood stem/progenitor cell transplantation (UCBT) in murine model.. 1 x 10(6) and 0.5 x 10(6) nucleated cells (NC) from C57BL/6 (H-2(b)) fetal and neonatal peripheral blood (FNPB) were separately transfused into lethally cyclophosphamide (380 mg/kg, ip) treated BALB/C (H-2(d)) recipients, 15 mg.kg(-1).d(-1) and 5 mg.kg(-1).d(-1) RA (15 mg and 5 mg RA) were administrated respectively 2 days before and after UCBT. Hematopoiesis and immune recovery, graft versus host disease (GVHD), engraftment and survival rates were then observed.. Hematopoiesis and immune recovery occurred faster in RA treated than in untreated mice (P < 0.05). Acute GVHD was absent. The levels of engraftment were higher in both 15 mg and 5 mg RA treated mice than those in untreated controls (P < 0.05). In 1 x 10(6) NC transfused mice, 15 mg and 5 mg RA could significantly increased the 30 and 60 days survival rates from 41.67% (without RA) to 72.23% and 70.83%, respectively (P < 0.05). In 0.5 x 10(6) cells transfused mice, 15 mg and 5 mg RA increased the survival rate from 14.29% (without RA) to 42.86% and 43.48%, respectively (P < 0.05), which were comparable to that of being transfused 1 x 10(6) cells without RA treatment (P > 0.05).. RA enhances the engraftment of umbilical cord blood stem/progenitor cells in murine model for UCBT. This might provide an experimental evidence of RA in clinical UCBT.

Topics: Animals; Cord Blood Stem Cell Transplantation; Female; Graft Survival; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Transplantation Conditioning; Transplantation, Heterologous; Tretinoin

Topical retinoic acid has proved to be of variable benefit in a number of dry eye disorders of disparate aetiology, in which squamous metaplasia with keratinization of ocular epithelium is present. Its exact role in patients with dry eye however remains in dispute. We describe a case of severe dry eye due to chronic graft-versus-host disease, which was refractory to conventional therapy but which responded remarkably to topical retinoic acid with reversal of conjunctival keratinization and marked resolution of symptoms.

Topics: Administration, Topical; Bone Marrow Transplantation; Chronic Disease; Dry Eye Syndromes; Graft vs Host Disease; Humans; Male; Middle Aged; Tretinoin

Chronic graft-versus-host disease (GVHD) of the skin is a common complication of allogeneic bone marrow transplantation. It can be resistant to common methods of systemic immunosuppression. We report successful treatment of a patient with progressive cutaneous GVHD that was resistant to cyclosporine and steroids after allogeneic marrow transplantation for acute myelogenous leukemia using topical tretinoin (Retin-A).

Topics: Administration, Topical; Adult; Bone Marrow Transplantation; Female; Graft vs Host Disease; Humans; Skin Diseases; Transplantation, Homologous; Tretinoin