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Diagnosis and Treatment
Published in Awanish Kumar, Ashwini Kumar, Diabetes, 2020
Regarding SPK, as per our current review of available literature, it is the most common procedure applied to brittle diabetic patients with severe renal dysfunction awaiting a pancreatic transplantation. On a technical front, different transplantation centres may have different surgical procedures, but most of them utilise the intraperitoneal segment for graft placement. While the pancreas is grafted into the right iliac fossa, the renal grafting is performed at contralateral iliac fossa. This procedure is said to be associated with less fluid accumulation around the grafted pancreas and better post-surgical wound healing [22]. Even in terms of using thymoglobulin (anti-human thymocyte antibody for T-cell depletion) for renal transplantation, it was reported that PTA patients received the highest dose, while SPK patients received the lowest dose [20]. But a few recent analyses have reported that PAK has a much better survival rate compared to T1DM patients with uraemia who are waiting for SPK [23–25]. Therefore, it can be interpreted based on various post-surgical meta-analyses that for patients who are awaiting a SPK with a waiting time more than 1 year, a PAK would be a better and feasible alternative if a living renal donor is available.
Intense Immunosuppression Followed by Autologous Stem Cell Transplantation in Severe Multiple Sclerosis Cases
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
G.L. Mancardi, R. Saccardi, A. Murialdo, F. Pagliai, F. Gualandi, A. Marmont, M. Inglese, P. Bruzzi, M.P. Sormani, M.G. Marrosu, G. Meucci, L. Massacesi, A. Bertolotto, A. Lugaresi, E. Merelli, M. Filippi
Neurological examinations (EDSS, Scripps) were scheduled at screening, baseline, before and after the mobilization regimen, after the conditioning regimen, every month for the following 6 months and then every three months until 24 months. Subsequently, patients were examined every 6 months. Peripheral blood progenitor cells (PBPCs) were mobilized with cyclophosphamide (CY) (4 gr/m2) followed by Filgrastim 5 μg/kg/day until the completion of the cell harvests. The immunoablative regimen was carried out within 30-40 days after mobilization. According to the protocol previously utilized by Fassas et al,8 the regimen consisted of BCNU 300 mg/m2 at day —7; Cytosine-Arabinoside 200mg/m2 and Etoposide 200 mg/m2 from day -6 to day-3 and Melphalan 140 mg/m2 at day-2. Rabbit ATG (Thymoglobulin, Sangstat), 5 mg/kg/day was administered at +1 and +2 as in vivo T-depletion. Intravenous cyclosporin A (1 mg/kg) was given during the conditioning regimen to prevent disease exacerbation due to cytokine release.
Transplantation immunology
Published in Gabriel Virella, Medical Immunology, 2019
Satish N. Nadig, Jane C. Kilkenny
Antithymocyte and antilymphocyte globulins were among the earliest successful therapeutic agents used in the management of graft rejection. These reagents are γ-globulin fractions separated from the sera of animals (rabbits, goats, or horses) injected with human thymic lymphocytes or human peripheral blood lymphocytes. Therefore, they are polyclonal and are directed against numerous cell surface epitopes on platelets, T and B cells, NK cells, macrophages, as well as adhesion molecules. They are very effective in the prevention and reversal of rejection episodes, and their mechanism of action is related to the destruction or inhibition of recipient lymphocytes. Their main drawbacks have been related to difficulty in obtaining standardized preparations, reactivity with other cell types, and frequent sensitization of the patients, which often leads to serum sickness when the globulins are administered repeatedly. However, the serum sickness has been greatly reduced by abandoning the horse preparation in favor of the rabbit preparation. Currently, the rabbit preparation is the most widely used and exhibits less batch variation than preparations from previous species. Thymoglobulin is used in situations where reversal of aggressive rejection is necessary, as well as cases where the patient is resistant to immunosuppression with steroids. Finally, this preparation is also used for pregraft induction, a process that involves suppression of immune cell proliferation prior to host exposure to graft antigens.
Outcomes of thymoglobulin versus basiliximab induction therapies in living donor kidney transplant recipients with mild to moderate immunological risk – a retrospective analysis of UNOS database
Published in Annals of Medicine, 2023
Hatem Ali, Mahmoud Mohammed, Tibor Fülöp, Shafi Malik
The initial Collaborative Transplant Study (CTS) analysis revealed that the major effect on transplant outcomes arose from mismatches in the HLA-DR [21, 22]. This was also noted in registry data studies performed using The United Kingdom Transplant Service and Eurotransplant registry data [23, 24]. Another study by Coupel et al. found that HLA-DR mismatches (and the number of rejection episodes) correlated with poor long-term survival [21]. Several immunosuppressive protocols have been implemented to overcome the detrimental effects of HLA mismatches. In the current era, tacrolimus and mycophenolate derivates (mycophenolate mofetil or enteric-coated mycophenolate sodium) are the core maintenance immunosuppressive therapies used worldwide. Thymoglobulin and basiliximab are the most widely used induction therapies [7, 8]. Thymoglobulin is usually reserved for high-risk transplants; however, it is not free of risk. It carries a higher risk of malignancy and serious opportunistic infections in comparison to basiliximab induction therapy [20].
Immunosuppressive therapy post-transplantation in children: what the clinician needs to know
Published in Expert Review of Clinical Immunology, 2020
Because of the redundancy of the immune system, polyclonal antibodies, which have a broad specificity, should theoretically be more effective in induction therapy than monoclonal antilymphocyte agents. Thymoglobulin is a rabbit-derived polyclonal antibody preparation approved for the treatment of rejection and recently also for induction therapy by the US Federal Drug Administration (FDA). Thymoglobulin contains antibodies to a wide variety of T-cell antigens and MHC antigens. Polyclonal antibodies act in three ways: By activating or altering the function of lymphocytes, by lysing lymphoid cells, and by altering the traffic of lymphoid cells and sequestering them. These antibodies are potently immunosuppressive, but often produce side effects. By triggering T cells, they generate significant first-dose effects, with the release of tumor necrosis factor alpha (TNFα), interferon γ (IFN-γ), and other cytokines, causing a first-dose reaction (flu-like syndrome, fever, and chills).
Belatacept/CTLA4Ig: an update and critical appraisal of preclinical and clinical results
Published in Expert Review of Clinical Immunology, 2018
Christoph Schwarz, Benedikt Mahr, Moritz Muckenhuber, Thomas Wekerle
In spite of encouraging results in clinical studies, the success of belatacept has been hampered by various factors, including the recently failed liver transplant trial. Currently, the most important goal is to reduce rejection rates under belatacept-based therapy. Thus, new strategies, drug dosing, and combination with potentially synergistic compounds need to be developed and investigated in the future to fully harness the potential of belatacept therapy. Several candidates have proven efficacy in experimental transplantation including mTOR inhibition with rapamycin [112], the sphingosine 1-phosphate receptor −1 (S1PR1) functional antagonist FTY720 [113], anti-LFA1 or anti-OX40L [114]. In clinical studies, the combination with thymoglobulin has shown promising results in order to reduce rejection rates [98]. Beyond that, the close interaction between CTLA4Ig and Tregs merits further investigation, as in the experimental setting, the immunosuppressive capacity of costimulation blockade with CTLA4Ig is at least partly Treg dependent [18]. These observations underline the caveat of combining belatacept with drugs, which are known to have a negative impact on Tregs including basiliximab [115] or CyA [116].