Stem cell therapy in treatment of different diseases

Stem cells are undifferentiated cells with the ability of proliferation, regeneration, conversion to differentiated cells and producing various tissues. Stem cells are divided into two categories of embryonic and adult. In another categorization stem cells are divided to Totipotent, Multipotent and Unipotent cells. So far usage of stem cells in treatment of various blood diseases has been studied [such as lymphoblastic leukemia, myeloid leukemia, thalassemia, multiple myeloma and cycle cell anemia]. In this paper the goal is evaluation of cell therapy in treatment of Parkinson's disease, Amyotrophic lateral sclerosis, Alzheimer, Stroke, Spinal Cord Injury, Multiple Sclerosis, Radiation Induced Intestinal Injury, Inflammatory Bowel Disease, Liver Disease, Duchenne Muscular Dystrophy, Diabetes, Heart Disease, Bone Disease, Renal Disease, Chronic Wounds, Graft-Versus-Host Disease, Sepsis and Respiratory diseases. It should be mentioned that some disease that are the target of cell therapy are discussed in this article

Anti-HLA antibodies and kidney allograft outcomes in recipients with donor bone marrow cell infusion

Anti-HLA-antibodies are known to affect the allograft survival in transplant recipient patients. The aim of this study was to evaluate the association between anti-HLA antibodies and kidney allograft outcomes, particularly in recipients with concurrent donor bone marrow cell infusion [DBMI]. Between June 2006 and May 2007, forty living unrelated donor kidney transplants consisting of 20 recipients with DBMI and 20 without infusion entered into the study and were monitored prospectively for one year. Pre-and post-transplant [days 14, 30, and 90] sera were screened for the presence of anti-HLA class-I and II antibodies, and subsequently positive sera retested with ELISA specific panel for antibody specification. Of 40 patients, 9 [22.5%] experienced acute rejection episodes [ARE] [6/20 cases in non-infused versus 3/20 in DBMI patients]. The prevalence of anti-HLA antibodies before and after transplantation were higher in patients with ARE compared to non-rejecting ones [88.8% vs. 38.7%, p=0.01 and 66.6% vs. 25.8%, p=0.04, respectively]. A total of 10% [4/40] of patients developed donor specific anti-HLA antibodies [DSA] and in this regard 2 patients from the control group experienced ARE. All 3 rejecting patients in DBMI group were negative for DSA and positive for non-DSA. The lower titer of post-transplant anti-HLA antibodies were shown in DBMI patients compared to pre-transplantation titer. Additionally, the average serum creatinine levels during one year follow up and even in those patients with ARE were lower compared to controls. Our findings reveal an association between pre-and post-transplant anti-HLA antibodies, and ARE and also early allograft dysfunction. It suggests that lower incidence of ARE, undetectable DSA, lower titer of antibodies concomitant with a decrease in serum creatinine level, better allograft function and lower percentages of PRA in DBMI patients, could be the probable manifestations of partial hypo-responsiveness against allografts

High frequency of clinically significant infections and cytomegalovirus disease in kidney transplant recipients with serum mannose-binding lectin deficiency

Mannose-binding lectin [MBL] constitutes defense against infections when adaptive immune response is compromised. Elevation in serum MBL levels has been shown in patients with kidney failure. We compared serum MBL levels before and after kidney transplant and evaluated association of MBL deficiency with infectious complications in kidney transplant recipients. This study was performed in 71 kidney transplant recipients and 48 healthy controls. In 36 recipients [group 1], serum MBL levels were tested before and on days 7 and 14 after transplantation. They were followed up for 6 months. In 35 recipients [group 2], serum MBL was measured during their posttransplant follow-up visits. In both groups, frequencies of clinically significant infections and acute rejection were compared between those with low MBL [< 500 ng/mL] and normal/high MBL [< 500 ng/mL]. Serum MBL levels [1744 +/- 905 ng/mL] were not higher in group 1 before transplantation than in controls. One and 2 weeks after transplantation, MBL levels decreased to 1699 +/- 1030 ng/mL and 1562 +/- 1020 ng/mL, respectively. Five patients who had low serum MBL levels experienced more frequent episodes of infections [P = .008] and CMV disease [P < .001]. Ten patients in group 2 with low MBL levels had more frequent episodes of CMV disease [P = .01]. These findings suggest a potential role for MBL in defense against developing posttransplant CMV disease and that low serum MBL levels in kidney transplant recipients be considered an indicator of the need for CMV prophylaxis

Autologous in vitro expanded mesenchymal stem cell therapy for human old myocardial infarction

Stem cell transplantation after myocardial infarction has been claimed to restore cardiac function. Mesenchymal stem cells attract a lot of attention because of the feasibility of in vivo and ex vivo differentiation to cardiomyocytes and endothelial cells as well as their trophic effect on tissue repair. In this study, we investigated the efficacy of autologous bone marrow derived mesenchymal stem cells in improving heart function in patients with old myocardial infarction. Eight patients with old myocardial infarction and proper inclusion criteria were injected with mesenchymal stem cells at the time of coronary artery bypass grafting or percutaneous coronary intervention [test group] and compared with eight matched patients who received the same treatment without mesenchymal stem cell injection [control group]. Evaluation of heart function was done by echocardiography plus single-photon emission computed tomography before and six months after the procedure. Serial clinical examination was performed every month through New York Heart Association class. The mean New York Heart Association class and single-photon emission computed tomography scan results decreased significantly in the test group [P=0.000 and 0.002, respectively] and in the control group [P=0.049 and 0.007, respectively] after the procedure at six months follow-up. Left ventricular ejection fraction increased significantly in the test group [P< 0.005] but not in the control group. In comparison between the test and control groups the results of New York Heart Association class assessment and single-photon emission computed tomography demonstrated significant improvement in the test group [P=0.005 and 0.013, respectively]. There were no significant differences between the baseline variables in the two groups. In conclusion transplantation of ex vivo expanded bone marrow derived mesenchymal stem cell in patients with old myocardial infarction is a safe and feasible procedure. These cells improve the cardiac fimction without serious adverse effects

Association of HLA class II alleles with childhood asthma and total IgE levels

Asthma is a complex and multifactorial disorder. Several studies have reported association between different HLA- DQB1 and HLA- DRB1 alleles and allergic asthma. The aim of the present study was to investigate the association of HLA-class II alleles and haplotypes, with total serum IgE and the results of the skin prick test in Iranian children with allergic asthma. A total of 112 patients with allergic asthma symptoms [75 males and 37 females] were selected randomly from the pediatric hospital. In some patients total serum IgE and prick test were determined. Data of this study shows that HLA-DRB1*12 significantly increased in asthmatic patients [4.5% vs. 0%, P-value=0.04]. HLA-DQB1*0603 and 0604 alleles were significantly higher in asthmatics than those in normal controls [10% vs. 0%, P-value= 0.0001; and 9.3% vs. 3.7%, P-value= 0.04, respectively]. The statistical significance was relinquished after p value correction for all alleles except for HLA-DQB1*0602 [Pc=0.03] and HLA-DQB1*0603 [Pc=0.0015]. Conversely, HLA-DQB1*0501 and 0602 were decreased in asthmatics compared to normal controls [7.5% vs. 13.5%, P-value= 0.05; and 4% vs. 12.5%, P-value= 0.002, respectively]. The mean of total IgE in patients was 483 IU, and it was significantly high about 1140 IU in asthmatic patients with positive skin prick test to house dust. The most frequent alleles in asthmatic patients with the total IgE>200 IU/mL were HLA-DRB1*11and 1401, HLA-DQA1*0505, HLA-DQB1*0301 and in patients with total IgE<200 IU/mL were HLA-DRB1*0301, 07 and 1301, HLADQA1*0201 and 0301, HLA-DQB1*0201. These data suggests that HLA-DRB1, DQA1 and DQB1 alleles and haplotypes might be implicated in susceptibility to allergy and asthma and serum IgE production. As asthma and atopy are multifactorial disorders, probably HLA genes are involved in the regulation of immune specific responses to common allergen

Does mesenchymal stem cell therapy help multiple sclerosis patients? report of a pilot study

Mesenchymal stem cells [MSCs] with their potential to differentiate into mesodermal and non-mesodermal lineages have several immunomodulatory characteristics. These properties make them promising tools in cell and gene therapy. To evaluate the potential therapeutic applications of autologous MSC in improving clinical manifestations of MS patients. Ten patients were included in this pilot study. All had progressive disease that had not responded to disease modifying agents including Mitoxantrone. Their Expanded Disability Status Scale [EDSS] score ranged from 3.5 to 6. Patients were injected intrathecally with culture expanded MSCs. They were followed with monthly neurological assessment and a MRI scan at the end of the first year. During 13 to 26 months of follow up [mean: 19 months], the EDSS of one patient improved from 5 to 2.5 score. Four patients showed no change in EDSS. Five patients' EDSS increased from 0.5 to 2.5. In the functional system assessment, six patients showed some degree of improvement in their sensory, pyramidal, and cerebellar functions. One showed no difference in clinical assessment and three deteriorated. The result of MRI assessment after 12 months was as following: seven patients with no difference, two showed an extra plaque, and one patient showed decrease in the number of plaques. This preliminary report emphasizes on the feasibility of autologous MSC for treatment of MS patients. However, in order to draw a definitive conclusion a larger sample size is required

Chimerism: a new look

Microchimerism has become a familiar term in the past few years. Many groups all over the globe, specializing in a diverse array of basic and medical sciences, have turned their attention to microchimerism, its possible role in disease or repair, and its mechanism of action in the host body. We reviewed the current knowledge about this novel term. We search the PubMed, using all the derivatives of chimera. All papers and their bibliographic information published by December 2005 were reviewed and 61 were selected. Microchimerism is the presence of foreign or nonhost cells in a body. These are cells that live, differentiate, and persist in the host body by definition. These cells can enter the host body in a variety of manners. The most familiar aspect is microchimerism resulting from organ transplant. For many years now scientists have been debating over the interpretation of this phenomenon. We know that donor cell engraftment in the recipient body is a sign of transplantation success. What this means is that the body has developed tolerance toward the foreign organ and created a chimer. How long this chimeric state will last, whether these cells will induce or be induced to create a chronic complication in the long run, or will these genetically distinct cell types live peacefully in one body to the end of the host's life are the essence of the ongoing discussion and what probes researchers to continue their search

HLA class II allele and haplotype frequencies in Iranian patients with leukemia

Previous studies demonstrated significant differences in a number of HLA allele frequencies in leukemia patients and normal subjects. In this study, we have analyzed HLA class II alleles and haplotypes in 110 leukemia patients [60 acute myelogenous leukemia "AML", 50 chronic myelogenous leukemia"CML"] and 180 unrelated normal subjects. Blood samples were collected from all of the patients and control subjects. DNA was extracted by salting out method and HLA typing was performed using PCR-SSP method. Significant positive association with AML was obtained for HLA-DRB1*11allele [35% vs. 24.7%, P=0.033]. Two alleles including HLA-DRB4 and-DQB1*0303 were significantly less frequent in AML patients than in controls. HLA-DQB1*0303 allele was never observed in CML patients compared with allele frequency in controls [4.2%]. According to haplotype analysis, HLA-DRB1*0101/DQA1*0104/-DQB1*0501 frequencies were significantly higher and-DRB1*16/-DQA1*01021/-DQB1*0501 frequencies were significantly lower in CML patients than in controls .In conclusion it is suggested that HLA-DRB1*16 allele and HLA-DRB1*15/-DQA1*0103/-DQB1*06011 and-DRB1*16/-DQA1*01021/-DQB1*0501 haplotypes predispose individuals to AML and HLA-DRB4 allele predispose to CML. Future studies are needed to confirm these results and establish the role of these associations in AML and CML

Human leukocyte antigen profile of two ethnic groups in southeast of Iran

This study was performed to determine the genetic diversity of HLA class I and II alleles among two ethnic groups in Southeastern Iran. HLA profiles were determined in 71 Iranian populations [41 Zaboli and 30 Baloch]. The frequencies of HLA-A02 [p=0.017],-Cw4 [p=0.003], and-DR8 [p=0.025] in the Zaboli populations were significantly higher than that in Baloch ethnic group. In contrast, the frequency of HLA-A23 allele was more frequent in Baloch than Zaboli [p=0.020]. This report represents an important resource for investigators in the fields of transplantation immunology and population genetics from widely dispersed areas of Iran

Cytokine gene polymorphisms in iranian patients with beta-thalassemia major

beta-thalassemia as a hereditary disease is defined as defective synthesis of beta -globin chains, resulting in erythropoiesis abnormalities and severe anemia. Different studies have shown that cytokines and cytokine gene polymorphisms play a major role in the pathogenesis of beta -thalassemia. Single nucleotide polymorphisms [SNPs] within the promoter region or other regulatory sequences of cytokine genes lead to overall production of cytokines. To analyze the genetic profile of Thl and Th2 cytokines in Iranian patients with beta -thalassemia major. Allelic and genotype frequencies of cytokine genes were determined in 30 thalassemia patients and 40 healthy subjects using PCR-SSP assay. Allele and genotype frequencies were calculated and compared with those of normal controls. The results of our study show a significant decrease in A allele at position UTR 5644 IFN-y, G alleles at position -238 TNF-oc and 166 IL-2, and C allele at position -590 IL-4. TGF- beta haplotype TG/TG increased whereas TGF- beta haplotype CG/CG and IL-10 haplotype GCC/ACC decreased significantly in all patients. Data of this investigation suggest that variations among cytokine gene polymorphisms may contribute to the disease susceptibility. A finding which needs to be fairly clarified in other ethnic groups

Prediction of rejection in renal transplantation by immune parameters

Monitoring of phenotypic characteristics of T-lymphocytes in peripheral blood is commonly performed to give the clinical parameters in the management of kidney transplant recipients. To predict rejection in renal transplantation by immune parameters. 16 non-diabetic kidney transplant candidates [4 females and 12 males, age = 20-65 yr,-first time transplant] were selected. The transplanted patients were divided into two groups based on the rejection during 3 weeks post transplant: group I [n = 9] without rejection and group II [n = 7] with a rejection episode. Immune parameters including lymphocytes subpopulations [by flowcytometry] and immunoglobulin classes [IgM, IgG, IgA and IgE by nephlometric assay] before and 45 days after transplantation were determined. The results of this investigation showed that the level of immunoglobulin IgG, IgM, IgA and IgE decreased post transplantation due to immunosuppressive drugs. CDS, CD4, CDS T cells count, CD56 NK cells count and CD20 B cells count pre- and post-transplantation did not show any significant differences. The amount of IgE [220 vs. 462 Ill/ml], CDS [62% vs. 69.7%] and CD4 [35% vs. 41.3%] cells increased in group II during rejection episode pre-transplantation. In addition, IgA increased pre-transplantation in group I those without rejection episode in comparison with group II with a rejection episode. Forty five days post transplantation IgA [209 vs. 152 mg/dl], IgG [1009 vs. 703 mg/dl] and CD20 [15% vs. 10%] increased in group 1 patients. It is suggestive that pre-transplantation increases IgE, CDS and CD4 are predictive of acute rejection

Ethics of tissue and stem cell trasplantation

Tissue and cell transplantation are regarded as a popular procedure in clinical sciences, prospecting a new horizon for several incurable diseases. Along with its usefulness, many ethical concerns accompany this development. The ethical issue of organ transplant is unique to the source used which includes: living related, living unrelated, cadaveric, and xenotransplant. Obtaining organs has a separate set of ethical concerns which are discussed under two headings, namely salvage and donation. Then there is the issue of organ marketing and the ethical, social, and economical issues it encompasses. All these are active areas of debate, and we have touched upon them by turn. This century has brought a new aspect of transplantation into the light, stem cell transplantation. Here we present some work done recently on mesenchymal stem cells and their outcome. These cells are now being employed in the therapy of some incurable ailments. It seems this kind of transplantation, although possessing its own range of issues, could prove to be the way of the future

Th1 and Th2 cytokine gene polymorphism in Iranian patients with chronic myelogenous leukemia

Bakground: lt has been hypothesized that genetic factors other than histocompatibility disparity may play a role in predisposition to developing Chronic Myelogenous Leukemia [CML]. In this regard, Thl and Th2 cytokines and their gene polymorphism seems to be important. Overall expression and secretion of cytokines is dependent, at least in part, on genetic polymorphism [nucleotide variations] within the promoter region or other regulatory sequences of cytokine genes. The majority of polymorphisms described are single nucleotide polymorphism [SNPs]. The objective of this study was to analyze the genetic profile of Thl and Th2 cytokines in 30 Iranian patients with CML and 40 healthy subjects

Methods: In the patients and control subjects, the allelic and genotype frequencies were determined for the cytokine genes. All typing were performed by PCR-SSP assay. Allele and genotype frequencies were calculated and compared with those of normal controls

Results: The results showed that the most frequent alleles in our patients were TGF-3 TG/TG, IL-4 T at position -1089, C at position -590, T at position -33 and IL-10 A at position -1082. Whereas the following alleles - TGF-3 CG/CG and IL-10 C at position -592 - were seen in much lower frequencies

Conclusion: In conclusion, it could be suggested that the frequency of high producing TGF-3 alleles and low producing IL-4 and IL-10 alleles in the CML patients is higher than the normal subjects

Microchimerism and renal transplantation: doubt still persists

Background: The Presence of donor leukocytes in recipients of organ allograft has been shown even several years after transplantation. However, it remains unclear whether this donor cell microchimerism plays an effective role in allograft acceptance or is simply a consequence of immunosuppressive conditions in recipients

Objective: To study microchimerism in a group of kidney transplant recipients

Methods: In this study, the Peripheral Blood Microchimerism [PBM] after renal transplantation was retrospectively evaluated in 32 male-to-female recipients of living [unrelated] and cadaveric donor renal transplants. Using a Nested Polymerase Chain Reaction [Nested-PCR] amplification specific for SRY region of the Y chromosome, microchimerism was detected with a sensitivity of 1:1000000. Recipients were classified and compared according to the presence of PBM, acute and chronic rejection episodes, type of allotransplant, recipient and donor age at transplantation, previous male labor or blood transfusion, allograft function [serum creatinine level], and body mass index

Results: Among 32 recipients, 7 [21.9] were positive for PBM in multiple testing at different post-transplantation times. All microchimeric recipients had received kidney from living-unrelated donors. No significant difference was observed with regard to other parameters mentioned above. In addition, acute rejection rate in the microchimeric group was 3 [42%] versus 4 [16%] in the nonmicrochimeric recipients [not significant]

Conclssion: Our results demonstrate better establishment of microchimerism after living donor kidney transplantation. However, concerning the true effect of microchimerism after renal transplantation doubt still persists; and it seems that microchimerism alone has no major protective role in renal allograft survival

Human leukocyte antigen profile in the Zaboli ethnic group living in the South-East Region of Iran

The human leukocyte antigen has become a key component in investigating the genetic relationships between populations. The aim of this study was to determine the genetic diversity of HLA class I and II alleles among Zaboli ethnic group of South-east Iran to establish a database for further investigations on ancestry and the genetic factors contributing to complex diseases in this region. Unrelated individuals from the Southeast geographic location throughout Iran were serologically typed using standard microcytotoxicity assays with commercial and local trays. The ethnic background of each individual was self-defined. HLA profiles were determined in 41 Zaboli populations. The most frequent class I alleles of the Zaboli ethnic group being the following: HLA-A1 [34.1%], -A2 [58.5%], -A11 [29.3%], -A24 [23.9%], -B5 [70.7%], -B16 [26.8%], and -Cw4 [24.4%]. The class II alleles more frequently observed in this group were HLA-DR1 [26.8%], -DR2 [26.8%], -DR3 [31.7%], -DR4 [29.3%], -DR7 [24.4%], -DR8 [22%], -DR11 [48.8%], -DRw52 [73.2%], -DRw53 [53.7%], -DQ1 [53.7%], -DQ2 [31.7%], and -DQ3 [29.3%]. This report utilized a first study of HLA class I and II typed individuals, from widely dispersed areas of Iran. This will help in studies related to disease associations and cadaver organ allocation programmes

Evaluation of Anti- HLA Class I antibodies in chronic rejection of kidney transplantation

Studies have shown that patients who do not produce donor specific and / or panel reactive anti-HLA antibodies have a longer graft survival. The purpose of this study was to evaluate the posttransplant humoral immune response towards HLA-class I antigens and the measurement of the serum creatinine levels which are used in monitoring posttransplant function of kidney. Serum samples from 132 renal transplant recipients were screened for preformed anti-HLA class I panel reactive antibodies [PRA] by means of microlymphocytotoxicity assay. The results revealed the presence of PRA in 26 [19.7%] out of 132 transplanted patients. Graft function was evaluated by measurement of serum creatinine levels which revealed the mean of 1.75 mg/di [SD: 1.08]. Because of clinical significance of presence of different PRA amounts [>10%, > 20% and >50% of panel reactivity] in patients, correlation with kidney function status was analyzed. The obtained data highlighted a higher presence of serum creatinine levels in PRA-positive patients compared to negative patients [P<0.01]. These results [and further studies for class II, ...] can be used to implement new therapeutic strategies to curtail post transplant alloantibodies production and better allografts survival

Cytokines genes polymorphisms in Iranian patiets with pulmonary tuberculosis

Pulmonary tuberculosis [PTB] has recently become a major problem in developed countries especially in immune compromised HIV infected individuals. Cytokines, their genes and receptors have been implicated in the protective immunity, pathophysiology and development of tuberculosis. In the present study the genotype frequencies of a number of polymorphic genes coding for cytokines or for cytokine receptors have been investigated in a case control study including a group of 40 Iranian PTB patients and 40 healthy individuals. The allelic polymorphism of cytokines SNPs were analyzed according to the protocols of the cytokine component designed for the 13th IHW by the Heidelberg University group. Using PCR-SSP method the following cytokine genes have been determined: IL-1 alpha [T/C -889], IL-1 beta [C/T +3962], IL-1R [C/T pstI 1970], IL-1RA [T/C mspaI 1100], IL-4RA [G/A+1902], IL- 12 [C/A -1188], TGF-beta [C/T codon 10, G/C codon 25], TNF-alpha [G/A -308, G/A -238], IL-2 [T/G -330 G/T +166], IL-4 [T/G -1098, T/C -590, T/C -33], IL-6 [G/C -174, G/A nt 560], IL-10 [G/A -1082, C/T -819, C/A -592]. From IL-1R cluster [pro- inflammatory cytokines] a positive significant association was found at position pstI 1970 C/T polymorphism where the C allele was over presented in the PTB patients [60% vs. 37.5%, P = 0.04].A significant negative association at codon 10 TGF-beta C/T polymorphism has also been shown in our patients, where the T allele was not detected in the patients but 10% of the control subjects expressed this allele [Fisher exact test, P = 0.05]. At this codon allele T [Leucine substitution] is associated with high TGF-beta production. For TNF alpha an insignificant tendency was found at position -308 A/G polymorphism where the G allele carried by 80% of cases and 65% of controls [P = 0.07].At position -238 a negative association was found at the GA polymorphism [10% vs. 25%, P = 0.07]. For IL-6 an insignificant positive association at position -174 C/G polymorphism, G allele [57.5% vs. 37.5, P = 0.07] was found. At the other cytokine genes no specific association were found. In conclusion it is suggested that C allele at position pstI 1970 of IL-1 cluster increases and T allele at codon 10 of TGF-beta decreases in PTB patients