Njurtransplantation är det enda botande behandlingsalternativet för patienter som befinner sig i kronisk njursviktsstadium 5. Dagens mest använda immunsuppressiva kombinationsbehandling i klinisk praxis består av calcineurinhämmaren takrolimus, mykofenolatmofetil och kortikosteroider i form av prednisolon. Belatacept (Nulojix®) är ett fusionsprotein som introducerades på marknaden 2011 och ska ses som ett alternativ för primär immunsuppressiv behandling. Verkningsmekanismen för belatacept är att hämma aktiveringen av T-celler genom blockera co-stimulatoriska signaler från antigenpresenterande celler. Teorin bakom belatacept är att man genom en mer specifik immunsuppression ska kunna undvika de nefrotoxiska biverkningar som calcineurinhämmarna takrolimus(Prograf®) och ciklosporin(Sandimmun®) ofta ger. Nefrotoxicitet kan på långsikt leda till en försämring av njurfunktion vilket på sikt kan leda till förlust av transplantatet. Syftet med detta arbete var att undersöka effektiviteten av belatacept jämfört med calcineurinhämmare med avseende på graftöverlevnad, njurfunktion och förekomsten av akuta rejektioner. Detta arbete är en litteraturstudie som gjorts genom att utvärdera fem studier som hittades på sökdatabasen PubMed. Samtliga studier som utvärderades i detta arbete påvisade inga signifikanta skillnader i graftöverlevnad mellan de patienter som behandlades med belatacept och de som behandlades med en calcineurinhämmare. Samtliga studier påvisade en signifikant högre njurfunktion mätt i cGFR, Calculated Glomerular Filtration Rate, hos patienter som behandlades med belatacept. Hos dessa patienter ökade njurfunktionen över tid vilket bekräftar teorin bakom belatacept som säger att man genom att undvika nefrotoxicitet ska kunna behålla en stabil nivå i njurfunktion.  I samtliga studier förutom i studie 2 så har patientgrupperna som mottagit belatacept drabbats av en högre incidens av akuta rejektioner där nästan alla skedde inom de första sex månader efter transplantation vilka oftast ger lindriga komplikationer. Slutsatserna som kan dras är att belatacept ger en högre njurfunktion på lång sikt vilket gör det mycket fördelaktigt framför calcineurinhämmare. Belatacept är förenat med ökad förekomst av akuta rejektioner men fördelen med den höga njurfunktionen kan anses väga tyngre då akuta rejektioner oftast ger lindriga komplikationer. Då belatacept är ett nytt läkemedel så kommer det behövas längre studier framöver för att påvisa en högre graftöverlevnad. / Kidney transplant is the only curing treatment for patients who have chronic kidney disease stage 5. Today’s most used immunosuppressive treatment after kidney transplant in Sweden and worldwide is the combination of the calcineurin inhibitor tacrolimus, mycophenolate mofetil and corticosteroids. Belatacept (Nulojix®) is a fusion protein which was introduced on the pharmaceutical market 2011 and should be viewed as an alternative for primary immunosuppressive treatment after kidney transplant. The mechanism of action for belatacept is to inhibit the activation of T-cells by blocking co-stimulatory signals provided by antigen-presenting cells. The theory behind belatacept is to avoid the nephrotoxic adverse events through a more specific immunosuppression. Nephrotoxicity is often seen with the calcineurin inhibitors tacrolimus (Prograf®) and cyclosporine (Sandimmune®). The consequence of nephrotoxicity is a deterioration in renal function which in a long-term can lead to graft loss. The aim of this study is to evaluate the efficacy of belatacept in comparison to calcineurininhibitors regarding graft survival, renal function and the occurrence of acute rejections. This literature study was conducted by evaluating five studies found in the PubMed database. None of the studies that were evaluated in this study showed any significant differences in graft survival of the patients treated with belatacept compared to calcineurin inhibitors. All studies demonstrated a significantly higher renal function measured in cGFR among patients treated with belatacept. The renal function increased over time which confirms the theory behind belatacept, i.e., that you can keep a more stable renal function over time by avoiding nephrotoxicity. All studies except study 2 demonstrated a higher incidence of acute rejection among patients who received belatacept as treatment. Almost all acute rejections in each study occurred within the first 6 months of the study which most of the time give minor complications.The conclusion that can be drawn from this literature study is that treatment with belatacept results in a higher renal function which makes it favorable to calcineurin inhibitors. Treatment with belatacept also results in a higher incidence of acute rejections but the benefit of a higher renal function can be considered to outweigh the risk of acute rejection.4In order to observe a significant difference in graft survival between patients receiving belatacept and those receiving calcineurin inhibitors several and longer studies, including more patients, need to be conducted.

Bakgrund: Takrolimus (Tac) används främst som immunsuppressivt läkemedel genom oral behandling efter organtransplantation, framför allt levertransplantation och njurtransplantation. Tac administreras som andrahandsbehandling för medelsvår och svår atopisk dermatit genom topikal behandling med två olika styrkor 0,1% och 0,03%. Det har länge varit kontroversiellt om Tac är cancerframkallande och om det kan påverka cellcykeln. Syfte: Studien avser att redovisa förekomsten av cancerfall kopplat till långtidsanvändning av Tac för behandling för atopisk dermatit.  Metod och material: Examensarbetet utfördes som litteraturstudie där fyra kliniska studier analyserades. De fyra vetenskapliga studierna hämtades från databasen PubMed med sökorden ”tacrolimus cancer development” och ” tacrolimus atopic dermatitis”.  Resultat: Resultatet från de fyra kliniska studier som undersökte cancerrisken vid exponering för Tac vid behandling av atopisk dermatit visade att Tac svagt ökar risken för hudcancer. En av studierna visade att Tac ökar risken för T-cellslymfom, för användning av Tac och T-cellslymfom blev riskkvoten HR=3,13 (95%CI, 1,41 till 6,94), (P = 0,005). Studie tre som genomfördes hos barn visade att Tac inte ökade risk för cancer bland barn. I studie fyra framgick att incidensfrekvens (IR) ökade för alla lymfom och kutana T-cellslymfom (CTCL) ökade i takt med ökande av Tac dosen. I studie ett diagnostiserades 13 studiedeltagare med icke-melanomhudcancer (NMSC) bland 4761 vuxna. Patienter med ljus hy och med åldern över 50 år hade högre risk att drabbas av NMSC.    Slutsats: De utvalda studierna visade att cancerrisken vid utvärtes applicering av Tac för atopisk dermatit-behandling är låg men det finns ändå en liten risk på grund av att den systemiska exponeringen ökar när kroppsytan och appliceringsområde ökar. / ABSTRACT Background: Tacrolimus (Tac) is mainly used as an immunosuppressive drug through oral treatment after organ transplantation, especially liver transplantation and kidney transplantation. Tac is administered as a second-line treatment for moderate and severe atopic dermatitis through topical treatment with two different strengths 0.1% and 0.03%. It has long been controversial whether Tac is carcinogenic and whether it can affect the cell cycle. The aim: The study intends to report if the occurrence of cancer cases is linked to the long-term use of Tac for the treatment of atopic dermatitis Method and material: The degree project was carried out as a literature study where four clinical studies were analyzed. The four scientific studies were retrieved from the PubMed database with the keywords "tacrolimus cancer development" and "tacrolimus atopic dermatitis". Results: The results from the four clinical studies that investigated the cancer risk after exposure to Tac in the treatment of atopic dermatitis showed that Tac slightly increases the risk of skin cancer. One of the studies showed that Tac increases the risk of T-cell lymphoma, use of Tac and T-cell lymphoma resulted in HR=3.13 (95%CI, 1.41 to 6.94), (P = 0.005). Study number three conducted in children showed that Tac did not increase the risk of cancer among children. In study number four, it appeared that incidence rate (IR) increased for all lymphomas and cutaneous T-cell lymphoma (CTCL) increased as the Tac dose increased. In study number one, 13 study participants were diagnosed with non-melanoma skin cancer (NMSC) among 4761 adults. Patients with fair skin and aged over 50 years had a higher potential to suffer from NMSC.   Conclusion: The selected studies showed that the cancer risk with topical application of Tac for atopic dermatitis treatment is low, but there is still a small risk because the systemic exposure increases as the body surface and area of application increases.

The introduction of calcineurin inhibitors (CNI) into immunosuppressive regimens significantly improved patients prognosis after heart transplantation. Some of the most significant complications have been recognized, such as the development of arterial hypertension and renal impairment due to calcineurin inhibitor toxicity. The aim of the study was to compare the effect of the dual blockade of the renin-angiotensin system (dual RAS combination) with standard antihypertensive medication on blood pressure control. The second aim was to evaluate whether effective antihypertensive combination therapy (dual RAS or a standard antihypertensive drugs combination) would reduce the progression of chronic kidney disease in patients with chronic immunosuppressive prophylaxis. Treatment of arterial hypertension involving the combination of angiotensin-converting enzyme inhibitor (ACEi) and angiotensin II receptor blocker (ARB) was similarly effective compared to the standard combination of antihypertensives. Blood pressure treatment targets were achieved in both studies. Administration of antihypertensive combination therapy including dual blockade of RAS alleviated the progression of chronic renal disease in the experimental and clinical part, where the nephroprotective effect of dual RAS blockade...

The aim of our study was to simulate in rats all aspects and techniques used in our new clinical program of cryopreserved alloarterial transplantation and investigate the influence of two immunosuppressive protocols with tacrolimus on acute rejection of these allografts. Cryopreserved abdominal aortic grafts were transplanted between Brown-Norway and Lewis rats. Tacrolimus (0,2 mg/kg daily) was administered from day 1 to day 30 (TAC1) or from day 7 to day 30 (TAC7), respectively. No immunosuppressed isogeneic (ISO) and allogeneic (ALO) rats combination served as control. Aortal wall destruction and infiltration by immunocompetent cells (MHC II+ cells of recipient origin) was studied on day 30 after transplantation. Flow cytometry was used for the analysis of day 30 sera for the presence of donor specific anti-MHC class I and II antibodies. The aortal allografts in both immunosuppressed groups showed regular morphology of aortal wall with no depositions of immunoglobulin G on day 30. The adventitial infiltration of non-immunosuppressed aortal allografts by MHC class II positive cells of recipient origin was significantly higher (ALO 20,7±6,7 cells, P <0,001) compared to both immunosuppressed groups (TAC1 5,9±5,5 cells, TAC7 6,1±5,1 cells). Anti-MHC antibodies class I and II level in peripheral blood...

Neurological disorders affect more than 14% of the population worldwide and together with traumatic brain and spinal cord injuries represent major health, public and economic burden of the society. Incidence of inherited and idiopathic neurodegenerative disorders and acute CNS injuries is growing globally while neuroscience society is being challenged by numerous unanswered questions. Therefore, research of the CNS disorders is essential. Since animal models of the CNS diseases and injuries represent the key step in the conversion of the basic research to the clinics, we focused our work on generation of new animal models and on their use in pre-clinical research. We generated and characterized transgenic minipig model of Huntington's disease (HD) which represents the only successful establishment of a transgenic model of HD in minipig which should be valuable for testing of long term safety of HD therapeutics. Next, we crossed the well characterized R6/2 mouse HD model with the gad mouse model which lacks the expression of UCHL1 which led to results that support the theory of "protective" role of mutant huntingtin aggregates and suggest that UCHL1 function(s) may be affected in HD disturbing certain branches of Ubiquitin Proteasome System. Traumatic spinal cord injury and Amyotrophic Lateral...