OBJECTIVETo review the current research into Foxp3(+) regulatory T cells (Treg) cell surface molecules, plasticity of Treg cells and mechanisms of Treg cell suppression and to explore the possibilities to interfere in Treg cell suppression of anti-tumor immunity.

DATA SOURCESA literature search of all English articles was performed on the online electronic PubMed database dated 1995 to 2010. The keywords searched included: CD4(+)CD25(+)Foxp3(+) regulatory T lymphocytes, cancer, and immunotherapy. After finding relevant articles within these search limits, a manual search was conducted through the references from these articles.

STUDY SELECTIONArticles regarding the role of Treg cells in tumor immunity and the utility of Treg cells in tumor immunotherapy.

RESULTSThe results show that significant numbers of Treg cells are found in many tumors and it has been shown that the number of tumor infiltrating Treg cells correlates with adverse clinic outcomes. Treg cells are emerging as a key component of acquired tolerance to tumors.

CONCLUSIONSSeveral mechanisms of immunosuppression can be mediated by Treg cell function. Distinct immunosuppressive molecules expressed by Treg cells or diverse molecules related to Treg induction or migration represent potential drug targets for cancer immunotherapy.

Forkhead Transcription Factors ; metabolism ; Humans ; Immunosuppression ; methods ; Immunotherapy ; methods ; Neoplasms ; immunology ; therapy ; T-Lymphocytes, Regulatory ; metabolism

No abstract available.
Humans ; Immunosuppression ; *Kidney Transplantation/methods ; *Pancreas Transplantation/methods ; Patient Selection ; Treatment Outcome

Non-infectious uveitis is one of the leading causes of preventable blindness worldwide. Long-term immunosuppressive treatment is generally required to achieve durable control of inflammation in posterior and panuveitis. Although systemic corticosteroids have been the gold standard of immunosup- pressive treatment for uveitis since first introduced in 1950s, its side effects of long-term use often warrant an adjuvant treatment to reduce the dosage/duration of corticosteroids needed to maintain disease control. Conventional immunosuppressive drugs, classified into alkylating agent, antimetabolites and T cell inhibitors, have been widely used as corticosteroid-sparing agents, each with characteristic safety/tolerance profiles on different uveitis entities. Recently, biologic agents, which target specific molecules in immunopathogenesis of uveitis, have gained great interest as alternative treatments for refractory uveitis based on their favorable safety and effectiveness in a variety of uveitis entities. However, lack of large randomized controlled clinical trials, concerns about efficacy and safety of long-term usage, and economic burden are limiting the use of biologics in non-infectious uveitis. Local administration of immunosuppressive drugs (from corticosteroids to biologics) through intraocular drug delivery systems represent another direction for drug development and is now under intense investigation, but more evidences are needed to support their use as regular alternative treatments for uveitis. With the numerous choices belonging to different treatment modalities (conventional immunosuppressive agents, biologics and local drug delivery systems) on hand, the practice patterns have been reported to vary greatly from center to center. Factors influence uveitis specialists' choices of immunosuppressive agents may be complex and may include personal familiarity, treatment availability, safety/tolerability, effectiveness, patient compliance, cost concerns and suggestions from related specialists such as rheumatologists and pediatricians. The focus of this review is to provide an overview of each treatment modality on safety/tolerability and effectiveness, which are believed to be the two most important factors affecting treatment decision making.
Humans ; Immunosuppression ; methods ; Immunosuppressive Agents ; therapeutic use ; Uveitis ; immunology ; pathology ; therapy

No abstract available.
Animals ; Antibiotics, Antifungal/*therapeutic use ; Humans ; Immunosuppression/*methods ; Protein Structure, Tertiary ; T-Lymphocytes/*immunology ; *Transduction, Genetic

BACKGROUNDThe status of sensitization in kidney transplant recipients in the last 10 years and the trend of induction and maintenance therapy in patients of different panel-reactive antibody (PRA) levels have not been analyzed. The aim of this study was to investigate the current status of pre-transplant sensitization and its association with graft outcome.

METHODSA total of 155 570 kidney transplants reported to United Network for Organ Sharing (UNOS) during 2000 - 2009 were included in this study. We investigated the current status of pre-transplant sensitization and its association with graft outcome, and also compared the usage trend of 16 induction agents and 7 maintenance immunosuppressants in patients at different PRA levels. The difference of distributions of categorical variables between groups was investigated using the chi-square test. Unpaired t test or one-way analysis of variance (ANOVA) were used for numerical variables. The survival rates of transplant recipients were estimated using Kaplan-Meier methods and significance was determined by Log-rank test. Two-side P value < 0.05 was considered statistically significant. All statistical analyses were performed using STATA 10 with all available updates as of March 2010 (StataCorp LP, College Station, Texas 77845, USA).

RESULTSDespite the fact of the decreased percentages of kidney transplant recipients with presensitization history, the mean PRA levels of all kidney recipients has been increasing in the last 7 years, which was possibly due to the introduction of more sensitive antibody testing techniques. The percentage of patients with treated rejection episodes within one year post-transplant were significantly higher in sensitized patients (PRA = 50% - 100%:14.3% and PRA = 1% - 49%:13.9%) than in non-sensitized patients (12.4%). Both 1- and 5-year graft survival rates improved in the last 10 years; this was more significant in high PRA patients. Thymoglobulin was the most commonly used induction agent in last 10 years. Its users increased from 10% to 46% in non-sensitized patients, from 12% to 57% in PRA 1% - 49% patients, and from 19% to 63% in PRA 50% - 100% patients. The users of Campath, intravenous immunoglobulin (IVIG), and Rituximab have been increasing and reached 16%, 20%, and 11% in highly sensitized patients. In the last 5 years, steroid-free patients were 33% - 36%, 30% - 37%, and 10% - 25% for PRA 0, 1% - 49%, and 50% - 100% respectively. Almost 90% of patients were on Prograf at discharge. It seems that Myfortic users have been increasing since 2005 and it may soon replace mycophenolate mofetil (MMF) if long-term follow-up study conforms its safety and efficacy.

CONCLUSIONSApplication of sensitive antibody testing techniques increased the mean PRA levels of transplant recipients in spite of a decreased percentage of sensitized recipients. Induction and maintenance therapy differed in patients at different PRA levels.

Graft Rejection ; immunology ; Graft Survival ; immunology ; Humans ; Immunosuppression ; methods ; Immunosuppressive Agents ; therapeutic use ; Kidney Transplantation ; immunology

BACKGROUND: The relationship between hypertension and the lesion distribution of posterior reversible encephalopathy syndrome (PRES) is in debate. METHODS: Twenty patients with PRES which developed during chemotherapy or immunosuppression treatment for the control of underlying malignancy or auto-immune disorders were selected from the database. Data regarding brain images, clinical symptoms, co-morbid illnesses, and mean arterial pressure (MAP) at the pre-symptomatic period (one day before the symptom onset) and at the symptom onset were collected. Patients were divided into two groups according to the presence of pre-symptomatic hypertension. The lesion distribution degree was calculated by numerical method (involvement score [IS]) and compared with MAP. RESULTS: No significant differences of clinical symptoms were found between two groups. IS and onset period MAP were higher in the hypertensive group. Pre-symptomatic MAP correlated with onset period MAP and IS in total patients. No significant correlation was found between IS and onset period MAP. CONCLUSIONS: The PRES patient with hypertension in the pre-symptomatic period would show more spatially distributed brain lesions than the patient with stable blood pressure.
Arterial Pressure ; Blood Pressure ; Brain ; Drug Therapy ; Humans ; Hypertension ; Immunosuppression ; Methods ; Posterior Leukoencephalopathy Syndrome

Intestinal transplantation has been established as a treatment option for patients that suffer from intestinal failure with complications from total parenteral nutrition. It is still rapidly evolving and just reached a landmark of 1, 000 cases worldwide. Intestinal allografts can be transplanted as isolated, combined with the liver or as a part of a multivisceral allograft. Tacrolimus-based immunosuppression regimens have been used universally with improved outcomes. Clinical outcome in intestinal transplantation has improved significantly over time, impacted by refinement of surgical technique and novel immunosuppression. However rejection, infection, and technical complications still remain the most difficult barrier to improve patient and graft survival.
Acute Disease ; Graft Rejection/diagnosis ; Humans ; Immunosuppression ; Intestines/*transplantation ; Nutritional Support ; Organ Transplantation/methods ; Postoperative Care ; Viscera/*transplantation

BACKGROUND AND OBJECTIVES: Mesenchymal stem cells (MSCs) are used to treat autoimmune or inflammatory diseases. Our aim was to determine the immunomodulatory mechanisms elicited by MSCs during inflammation. METHODS AND RESULTS: We cocultured MSCs with peripheral blood mononuclear cells for a mixed lymphocyte reaction or stimulated them by phytohemagglutinin. Morphological changes of MSCs and secretion of acetylcholine (ACh) from MSCs were measured. The effects of an ACh antagonist and ACh agonist on lymphocyte proliferation and proinflammatory-cytokine production were determined. The inflammatory milieu created by immune-cell activation caused MSCs to adopt a neuronlike phenotype and induced them to release ACh. Additionally, nicotinic acetylcholine receptors (nAChRs) were upregulated in activated peripheral blood mononuclear cells. We observed that ACh bound to nAChR on activated immune cells and led to the inhibition of lymphocyte proliferation and of proinflammatory-cytokine production. MSC-mediated immunosuppression through ACh activity was reversed by an ACh antagonist called α-bungarotoxin, and lymphocyte proliferation was inhibited by an ACh agonist, ACh chloride. CONCLUSIONS: Our findings point to a novel immunomodulatory mechanism in which ACh secreted by MSCs under inflammatory conditions might modulate immune cells. This study may provide a novel method for the treatment of autoimmune diseases by means of MSCs.
Acetylcholine ; Autoimmune Diseases ; Humans ; Immunosuppression ; Inflammation ; Lymphocyte Culture Test, Mixed ; Lymphocytes ; Mesenchymal Stromal Cells ; Methods ; Phenotype ; Receptors, Nicotinic

OBJECTIVETo analyze the clinical features of mid- and long-term acute cardiac allograft rejection to improve the long-term clinical outcomes of the patients.

METHODSFourteen recipients (11 males and 3 females) underwent orthotopic heart transplantation with standard immunosuppressive therapy protocols (3 cases) or induction therapy protocols (11 cases). Cyclosporine, azathioprine or mycophenolate mofetil, and prednisolone were applied as the maintenance immunosuppressive regimen. Acute graft rejection episodes occurred within 3 to 6 months in 1 case, within 6 months to 1 year in 3 cases, within 1 to 2 years in 3 cases, within 2 to 5 years in 6 cases, and above 5 years in 1 case.

RESULTSNo significant difference was found in the incidence of late heart rejection between the patients receiving the two immunosuppressive therapy protocols. Immunosuppressants were withdrawn or spared in 8 recipients due to different causes. Nine recipients with steroid-sensitive acute cardiac allograft rejection were treated with steroid-pulse therapy, while the other 5 were treated with a short course of polyclonal antithymocyte antibodies because of steroid-resistant acute rejection; in 11 cases, azathioprine was converted to mycophenolate mofetil. Four of the 5 late deaths occurred in the recipients with steroid-resistant rejection. The surviving recipients had a good quality of life, and no recurrent episodes of rejection or infection were observed in the follow-up period.

CONCLUSIONSLate acute cardiac allograft rejection is associated mainly with patient compliance but not with early immunosuppressive therapy protocols. The episodes are rather severe and should be timely treated with steroid pulses or polyclonal antithymocyte antibodies.

Adolescent ; Adult ; Cyclosporine ; Female ; Graft Rejection ; etiology ; prevention & control ; Heart Transplantation ; adverse effects ; Humans ; Immunosuppression ; methods ; Male ; Middle Aged ; Mycophenolic Acid ; analogs & derivatives ; Young Adult

BACKGROUNDIn haploidentical hematopoietic stem cell transplantation (HSCT), the duration of graft-versus-host disease (GVHD) prophylaxis after modified donor lymphocyte infusion (DLI) was the only risk factor of DLI-associated grades 3-4 acute GVHD. However, the successful application of modified DLI depended not only on the reduction of severe GVHD, but also on the preservation of graft-versus-leukemia (GVL) effect. Therefore, this study was performed to compare the impact of prophylaxis for 6-8 weeks and prophylaxis for <6 weeks on GVL effect after modified DLI in haploidentical HSCT.

METHODSA total of 103 consecutive patients developing hematological relapse or minimal residual disease (MRD)-positive status after haploidentical HSCT and receiving modified DLI were investigated retrospectively. Fifty-two patients received prophylaxis for 6-8 weeks after modified DLI; the remaining 51 patients received prophylaxis for <6 weeks.

RESULTSFirst, compared with prophylaxis for <6 weeks, prophylaxis for 6-8 weeks reduced incidence of relapse in total patients (26.6% vs. 69.0%, P < 0.001). Besides, prophylaxis for 6-8 weeks also reduced incidence of relapse in 54 patients developing hematological relapse post-transplant (P = 0.018) and in 49 patients developing MRD-positive status post-transplant (P < 0.001). Second, prophylaxis for 6-8 weeks reduced incidence of acute GVHD (P < 0.05), reduced the therapeutic application of immunosuppressive agents (P = 0.019), but increased the incidence of chronic GVHD (P < 0.05). Third, prophylaxis for 6-8 weeks improved overall survival and disease-free survival in total patients, as well as in patients developing hematological relapse post-transplant and in patients developing MRD-positive status post-transplant (P < 0.05).

CONCLUSIONSIn haploidentical HSCT, prophylaxis for 6-8 weeks after modified DLI does not reduce GVL effect, but reduces the incidence of DLI-associated acute GVHD compared with prophylaxis for <6 weeks. This strategy will probably improve the safety and efficacy of modified DLI further.

Adolescent ; Adult ; Child ; Female ; Graft vs Host Disease ; prevention & control ; Hematopoietic Stem Cell Transplantation ; methods ; Humans ; Immunosuppression ; methods ; Leukemia ; therapy ; Male ; Middle Aged ; Neoplasm, Residual ; prevention & control ; Young Adult