Israel Medical Association Journal

Type 1 diabetes mellitus is caused by an autoimmune destruction of pancreatic islet beta cells, leading to insulin deficiency. Beta-cell replacement is considered the optimal treatment for type 1 diabetes, however it is severely limited by the shortage of human organ donors. An effective cell replacement strategy depends on the development of an abundant supply of beta cells and their protection from recurring immune destruction. Stem/progenitor cells, which can be expanded in tissue culture and induced to differentiate into multiple cell types, represent an attractive source for generation of cells with beta-cell properties: insulin biosynthesis, storage, and regulated secretion in response to physiologic signals. Embryonic stem cells have been shown to spontaneously differentiate into insulin-producing cells at a low frequency, and this capacity could be further enhanced by tissue culture conditions, soluble agents, and expression of dominant transcription factor genes. Progenitor cells from fetal and adult tissues, such as liver and bone marrow, have also been shown capable of differentiation towards the beta-cell phenotype in vivo, or following expression of dominant transcription factors in vitro. These approaches offer novel ways for generation of cells for transplantation into patients with type 1 diabetes.

In recent years, umbilical cord blood has emerged as an alternative source of hematopoietic progenitors (CD34+) for allogeneic stem cell transplantation, mainly in patients who lack an human leukocyte antigen-matched marrow donor. Since 1998, about 2,500 patients have received UCB[1] transplants for a variety of malignant and non-malignant diseases. The vast majority of recipients were children with an average weight of 20 kg, however more than 500 UCB transplantations have already been performed in adults. The “naive” nature of UCB lymphocytes may explain the lower incidence and severity of graft versus host disease encountered in UCBT[2] compared to the allogeneic transplant setting. Furthermore, UCB is rich in primitive CD16^-CD56⁺⁺ natural killer cells, which possess significant proliferative and cytotoxic capacities and can be expanded using interleukin-12 or 15, so as to mount a substantial graft versus leukemia effect. The major disadvantage of UCB is the low yield of stem cells, resulting in higher graft failure rates and slower time to engraftment compared to bone marrow transplantation. A rational approach thus involves ex vivo expansion of UCB-derived hematopoietic precursors.

Background: An organ sharing system should achieve fairness and optimal graft longevity. Balancing between social and utilitarian considerations is a sensitive ethical, public and medical issue that requires a means to examine the consequences of any allocation policy or planned changes thereof.

Objective: To evaluate the performance and applicability of a computerized simulation model by examining the impact of two opposing organ allocation policies (social or utilitarian) on predicted organ distribution regarding age, waiting time, recipient sensitization measured by panel reactive antibody level and overall donor-recipient tissue matching (measured by the number of HLA antigen mismatches).

Methods: Using a computerized simulation model, virtual donors and recipients were emulated and organs were allocated according to either social algorithms or utilitarian policies. The resulting number of HLA mismatches, PRA[1], age, and waiting time distributions were compared between allocation strategies.

Results: Simulating allocation of 7,000 organs to 17,000 candidate recipients and implementing social policies yielded donor-recipient compatibility comparable to utilitarian policies (0–1 mm: 19.4% vs. 28%) while allocating 66.7% of organs to long waiters (>48 months).

Conclusion: This computerized simulation model is a valuable tool for decision-makers establishing or modifying organ allocation policies.

Background: Recent advances in immunosuppressive therapy have led to a substantial improvement in the outcome of kidney transplantation. Living unrelated donors may become a source of additional organs for patients on the kidney waiting list.

Objectives: To study the impact of combination of calcineurin inhibitors and mycophenolate-mofetile, together with steroids, on outcomes of living related and unrelated transplants. 

Methods: Between September 1997 and January 2000, 129 patients underwent living related (n=80) or unrelated (n=49) kidney transplant. The mean follow-up was 28.2 months. Immunosuppressive protocols consisted of MMF[1] with cyclosporine (41%) or tacrolimus (59%), plus steroids. Patient and graft survival data, rejection rate, and graft functional parameters were compared between the groups.

Results: LUD[2] recipients were older (47.8 vs. 33.6 years) with higher number of re-transplants (24.5% vs. 11.2% in LRD[3] recipients, P < 0.05). Human leukocyte antigen matching was higher in LRD recipients (P < 0.001). Acute rejection developed in 28.6% of LUD and 27.5% of LRD transplants (P = NS). Creatinine levels at 1, 2 and 3 years post-transplant were 1.6, 1.7 and 1.7 mg/dl for LRD patients and 1.5, 1.5 and 1.3 mg/dl for LUD recipients (P = NS). There was no difference in patient survival rates between the groups. One, 2 and 3 year graft survival rates were similar in LRD (91.3%, 90% and 87.5%) and LUD (89.8%, 87.8% and 87.8%) recipients.

Conclusions: Despite HLA[4] disparity, rejection and survival rates of living unrelated transplants under current immunosuppressive protocols are comparable to those of living related transplants.

Background: Historically, donor age above 55 years has been considered to be a relative contraindication for organ transplantation. The shortage of organs for transplantation has led to the expansion of the donor pool by accepting older donors. 

Objectives: To compare the 1 year follow-up in patients after lung transplantation from older donors (>50 years old) and in patients after transplantation from younger donors (± 50 years).

Methods: The study group comprised all adult patients who underwent lung transplantation at the Rabin Medical Center between May 1997 and August 2001. Donors were classified into two groups according to their age: ≤ 50 years (n=20) and > 50 years (n=9). Survival, number and total days of hospitalization, development of bronchiolitis obliterans syndrome, and pulmonary function tests, were examined 1 year after transplantation.     

Results: We performed 29 lung transplantations in our center during the observed period. Donor age had no statistically significant impact on 1 year survival after lung transplantation. There was no statistically significant effect on lung function parameters, the incidence of hospitalization or the incidence of bronchiolitis obliterans between both donor age groups at 1 year after transplantation.

Conclusions: Donor age did not influence survival or important secondary end-points 1 year after lung transplantation. By liberalizing donor criteria of age up to 65 years, we can expand the donor pool, while assessing other possible mechanisms to increase donor availability. 

Intractable forms of autoimmune diseases follow a rapid course, with a significantly shortened life expectancy sometimes comparable to that of malignant diseases. Immunoablative therapy, including high dose cytotoxic agents and hematopoietic autologous stem cell rescue, was recently introduced as an aggressive approach to treat autoimmune diseases that have a rapid course and are resistant to conventional therapy. The most frequent indication for this type of treatment is multiple sclerosis, seconded by systemic sclerosis. The results of immunoablative treatment with documented responses in both diseases are encouraging. The data are mature enough to begin comparative randomized studies of immunoablative versus conventional treatment to validate the benefit of the aggressive approach. A randomized trial involving SSc[1] was recently launched (ASTIS) and a trial involving MS[2] is under preparation. Considerably less experience with immunoablative treatment has been gained in systemic lupus erythematosus, rheumatoid arthritis, and other disorders with an autoimmune pathophysiology. Autologous hematopoietic stem cell transplantation in humans offers more long-lasting immunosuppression than reeducation of lymphocytes. In fact, allogeneic transplantation may replace the whole immune system. However, this attractive approach is still associated with considerable morbidity and mortality and is not yet justified for treatment of automimmune diseases. Non-myeloablative allogeneic transplantation and sub-myeloblative high dose cyclophosphamide without stem cell support are alternative approaches that could be explored in pilot studies.

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