thymosin and Graft-vs-Host-Disease

We designed a phase I/II clinical study to determine safety and efficacy of thymosin alpha1 (Talpha1) administration in recipients of one HLA haplotype (haploidentical) stem cell transplants for hematologic malignancies. Talpha1 administration did not cause acute or chronic graft versus host disease and was associated with significant improvement in polymorphonuclear (phagocytosis) and dendritic cell (phagocytosis, expression of costimulatory molecules, and cytokine production) functions. It was also associated with increased T-cell counts and earlier appearance of functional pathogen-specific T cell responses (by a sensitive limiting dilution assay that detects frequency of T cells specific for Aspergillus, Candida, CMV, ADV, VZV, HSV, Toxoplasma). Five of six haploidentical transplant recipients who received Talpha1 are alive and disease free at a median follow-up of 10 months after transplantation (range: 5-20). They experienced only a single nonlethal infectious episode and one patient developed fatal immune hemolytic anemia. At this very early stage of the clinical trial, we conclude Talpha1 administration is safe and may impact favorably on immune function. Larger numbers of patients and longer follow-up are, of course, needed to assess its impact on survival.

Topics: Aspergillus; Dendritic Cells; Graft vs Host Disease; Haplotypes; Hematologic Neoplasms; Hematopoietic Stem Cells; Humans; Immunity; Infections; Simplexvirus; T-Lymphocytes; Thymalfasin; Thymosin

Standard therapies for severe dry eye are limited and fail to resolve the problem. The purpose of this study was to evaluate the safety and efficacy of Thymosin β4 eye drops (RGN-259) as a novel therapy for severe dry eye disease (including that associated with graft vs. host disease).. A small, multicenter, randomized, double-masked, placebo-controlled 56-day phase 2 clinical trial including a 28-day follow-up at 2 US sites. Nine patients with severe dry eye were treated with either RGN-259 (0.1%) or vehicle control 6 times daily over a period of 28 days. Dry eye sign and symptom assessments, such as ocular discomfort (using the OSDI questionnaire) and corneal fluorescein staining (using the NEI workshop grading system), were evaluated at various time points.. Statistically significant differences in both symptom and sign assessments, were seen at various time points throughout the study. Of particular note at day 56, the RGN-259-treated group (12 eyes) had 35.1% reduction of ocular discomfort compared with vehicle control (6 eyes) (P = 0.0141), and 59.1% reduction of total corneal fluorescein staining compared with vehicle control (P = 0.0108). Other improvements seen in the RGN-259-treated patients included tear film breakup time and increased tear volume production.. In this small trial, RGN-259 eye drops were safe and well tolerated and met key efficacy objectives with statistically significant symptom and sign improvements, compared with vehicle control, at various time intervals, including 28-days posttreatment. CLINICAL TRIAL REGISTRATION--URL: http://www.clinicaltrials.gov. Unique identifier: NCT01393132.

Topics: Adult; Aged; Cornea; Double-Blind Method; Dry Eye Syndromes; Female; Fluorescein; Fluorescent Dyes; Fluorophotometry; Follow-Up Studies; Graft vs Host Disease; Humans; Male; Microfilament Proteins; Middle Aged; Ophthalmic Solutions; Surveys and Questionnaires; Tears; Thymosin

Thymus tissue implants, thymic epithelial cells obtained from third party donors sharing one HLA-A and -B locus with the recipient, or the thymic hormones thymosin fraction 5 and thymopentin were given to recipients of HLA-identical sibling bone marrow to prevent chronic graft-versus-host disease (GVHD) and accelerate immunologic reconstitution. The clinical courses of 17 patients receiving thymus tissue and 18 patients receiving thymic hormones were reported initially 5 years ago and showed no difference in the incidence of chronic GVHD or immunologic recovery from those of concurrent or historical controls. We report here for the first time nine new patients who received thymus tissue implants with modifications of the culture method to lower the number of lymphocytes in the transplanted tissue with the intent of reducing rejection of the thymus tissue grafts. The clinical outcomes and immunologic functions of these nine patients were similar to those of the recipients of the earlier thymus tissue implants. With follow-up now ranging from 2.2 to 12.3 years (median 6.7) for the total group, 16 patients are alive. Seven never developed chronic GVHD. Nine were treated for chronic GVHD, seven of whom recovered and are leading normal lives, one has chronic pulmonary insufficiency, and one is disabled from chronic GVHD. We conclude that thymus tissue grafts or thymic epithelial cells partially HLA-matched to the recipient, thymosin fraction 5, or thymopentin used as described were not effective in reducing the incidence of chronic GVHD, improving immunologic recovery, or altering long-term survival.

Topics: Adolescent; Adult; Anemia, Aplastic; Bone Marrow Transplantation; Child; Clinical Trials as Topic; Female; Follow-Up Studies; Graft vs Host Disease; Humans; Leukemia; Male; Middle Aged; Peptide Fragments; Thymopentin; Thymopoietins; Thymosin; Thymus Gland; Thymus Hormones

The present study was designed to investigate the effect of thymosin α1 (Tα1) administration in infective recipients of hematopoietic stem cell transplantation (HSCT) for hematologic malignancies. Eight patients were enrolled in our study, including seven allo-HSCT patients and one auto-HSCT patient. These patients were allocated randomly into the treatment group (four cases) and control group (four cases). Tα1 was used in the treatment group to test its effectiveness in infection control. The concentrations of cytokines IFN-γ, IL-2, IL-4, IL-10, and IL-12 were observed, and the levels of CD3(+), CD4(+), and CD8(+) T cells, as well as of CD4(+)/CD8(+) and CD4(+)/CD25(+) regulatory T cell (Treg) were measured. When Tα1 was administered for 2 weeks, the concentrations of these cytokines were increased after 1 month in the treatment group. Interestingly, the levels of IFN-γ, IL-2, IL-10, and IL-12 were increased in the treatment group more than those in the control group, whereas there were no significant differences between the treatment and control group in the levels of CD3(+), CD4(+), and CD8(+) T cells, or in CD4(+)/CD8(+) or CD4(+)/CD25(+) Treg cells. Notably, Tα1 administration did not cause acute or chronic graft versus host disease (GVHD). We conclude that Tα1 administration is safe and may impact favorably on immune function, and that it may improve resistance to infection and induce immunotolerance without GVHD.

Topics: Adolescent; Adult; Cytokines; Female; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Infections; Male; Middle Aged; T-Lymphocyte Subsets; Thymalfasin; Thymosin; Treatment Outcome; Young Adult

Aging induces a number of changes in the immune system, including the involution of the thymus which results in the loss of thymic hormone production and alteration in T cell function. One age-dependent change in immune response is the increasing risk of developing acute or chronic form of graft-versus-host disease (GVHD) following bone marrow transplantation as the age of the recipient increases. A murine model of GVHD that has been extensively studied is one in which injection of C57BL/6 spleen cells into unirradiated B6D2F1 mice results in an acute form of GVHD characterized by cytolytic T lymphocytes (CTL), suppressor cells, runting, and occasionally death. In contrast, injection of DBA/2J spleen cells results in a chronic form of GVHD characterized by a lack of CTL and hyperproduction of immunoglobulin and autoantibodies. This study shows that the GVHD response of DBA/2J spleen cells is dependent on the age of the donor DBA/2J mice. If spleen cells from DBA/2J mice older than 3 months are injected into B6D2F1 recipients, CTL and lack of immunoglobulin production indicative of acute GVHD result. Administration of thymosin fraction 5, a collection of thymic hormones, to DBA/2J mice older than 3 months caused spleen cells from these treated mice to give a GVHD response characteristic of the chronic form of GVHD in B6D2F1 recipients. Thus, thymic hormones were able to modulate the changes in GVHD responses of DBA/2 lymphocytes that occur as the mice age. Preliminary fractionation of TF5 has indicated that there are at least two active thymic peptides present in TF5.

Topics: Aging; Animals; Chromatography, High Pressure Liquid; Disease Models, Animal; Dose-Response Relationship, Drug; Graft vs Host Disease; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Peptides; Thymosin

More than 1 year is required for immunologic function to recover following human marrow grafting. In an attempt to shorten the time required for immunologic reconstitution, 14 patients were treated with thymosin fraction 5 after transplantation. Two died before administration of thymosin could be completed. In the remaining 12 patients, immunologic studies were compared to those of patients who were transplanted but did not receive thymosin. While five patients had transient elevation of in vitro lymphocyte blastogenesis during thymosin treatment, results of other immunologic studies from patients treated with thymosin were similar to those from patients not treated. The subsequent development of graft-versus-host disease, major or minor infection, and leukaemic relapse was not different between the groups. Six patients are alive and five are well without problems; one has chronic graft-versus-host disease. We conclude that thymosin fraction 5 administered as described was not toxic. Although modifying some immunological parameters, thymosin did not appear to alter the incidence of graft-versus-host disease, infection or leukaemic relapse or to accelerate immunologic reconstitution.

Topics: Adolescent; Adult; Anemia, Aplastic; Antibody Formation; Bone Marrow Transplantation; Child; Graft vs Host Disease; Humans; Immunity, Cellular; Immunoglobulins; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Lymphocyte Activation; Rosette Formation; Thymalfasin; Thymosin; Time Factors