TOLERANCE WITHOUT MICROCHIMERISM: IS THAT POSSIBLE IN LIVER TRANSPLANTATION?

Abstract

Objective It is uncovered the relationship between microchimerism and liver graft tolerance. Many studies inspired the concept of microchimerism and tolerance in solid organ transplantation (SOT). Our aim is to explore this aspect in a strictly selected patients’ cohort on CD3+ cells to show the microhimerism disappearance prove the tolerance instead of presence of it. Materials and Methods We strictly selected liver transplantation patients treated with calcineurins inhibitors (cnis), with very low dose of drugs who has never developed documented rejection. The DNA extraction and microchimerism research method used was based on the discrimination of donor and recipient alleles by PCR amplification of microsatellite markers and capillary electrophoresis with fluorescence detection. Results Twelve patients with alcohol-induced cirrhosis without rejection or rejection-related complications during the post-operative course were selected. The immunosuppressive regimen included tacrolimus and mycophenolate mofetil. The blood residual tacrolimus concentration was under or equal 5 ng/L below normal. We described the count of white blood cells and selected CD3+ after the MACS separation procedure. In our study, we did not observe any microchimerism in none of the patients. Discussion We achieved that in case of absence of microchimerism with maintained biochemical stability we could choose to switch off the immunosuppressive therapy even the microchimerism accepted like a condition to the tolerance till our study. Consequently, it will be reduce the side effects of immunosuppressive treatment such as renal failure, metabolic disorders, diabetes mellitus and cancers and the patient's quality of life will be improved be decreased financial aspect of immunesuppressive treathment

Keywords

• Microchimerism
• Liver Transplantation
• Tolerence

KARACİĞER TRANSPLANTASYONUNDA MİKROKİMERİZM OLMADAN TOLERANS MÜMKÜN MÜDÜR?

Abstract

Amaç Karaciğer transplantasyonu sonrası tolerans kavramı son yıllarda giderek popülarite kazanmaktadır. Bu çalışmada amacımız çok özenli parametrelerle seçilmiş yaklaşık on yıllık bir seride düşük doz immünosupressif kullanan bir grupta toleransın varlığını CD3+ hücrelerde mikrokimerizmin yokluğu ile kanıtlamaya çalışmaktır. Gereç ve Yöntem Mikrokimerizm yokluğunu araştırma yöntemi; retrospektif olarak donör kanlarından cross match yapılarak DNA izolasyonunun ardından, mikrosatellit markerlarının PCR ile amplifikasyonu ve dönör ve alıcı allellerinin karşılaştırılması ilkesine dayanıyordu. Bulgular Postoperatif takiplerinde organ reddi ya da buna bağlı komplikasyonları olmayan alkole bağlı sirozu olan 12 hastadan bir izogrup oluşturuldu. Bu hastalar immunsüpresif olarak takrolimus ve mikofenolat mofetil kullanıyordu ve ilaç kan düzeyleri 5 ng/l yani kabul edilebilir sınırın altında idi. Çalışmamızda hiçbir hastamızda kimerizm gözlemlemedik. Sonuç Biyokimyasal stabiliteyi koruyan mikrokimerizmin yokluğu yani transplantasyona tolerans olması durumunda immunsupressif tedavilerin kesilebilir olmasının düşünülebilirliği gündeme gelmektedir.Böylelikle immünsüpressif tedavilerin yan etkileri azalacak ve hastalar böbrek yetmezliği, metabolik bozukluklar, diyabet ve kanserlerin artmış riskinden korunacak, dolayısı ile yaşam kalitesi artmış ve transplantasyon sonrası kullanılan ilaçların ülke ekonomisine yükü azalmış olacaktır.

Keywords

• mikrokimerizm
• karaciğer nakli
• tolerans

References

1. 1. Manzia TM, Angelico R, Gazia C, Lenci I, Milana M, Ademoyero OT.De novo malignancies after liver transplantation: The effect of immunosuppression-personal data and review of literature.World J Gastroenterol. 2019 Sep 21;25(35):5356-5375.
2. 2. Stolp J, Zaitsu M, and Kathryn J. Wood Immune Tolerance and Rejection in Organ Transplantation. Methods Mol Biol. 2019;1899:159-180.
3. 3. Wang P, Jiang Z, Wang C, Liu X, Li H, Xu D.Immune Tolerance Induction Using Cell-Based Strategies in Liver Transplantation: Clinical Perspectives. Front Immunol. 2020 Aug 18;11:1723.
4. 4. Mazariegos G.V, Immunosuppression Withdrawal After Liver Transplantation: What Are the Next Steps? Transplantation, 2011. 91: p. 697-699.
5. 5. Hotta K, Aoyama A, Oura T, Yamada Y, Tonsho M, Huh KH. Induced Regulatory T Cells in Allograft Tolerance via Transient Mixed Chimerism JCI Insight . 2016 Jul 7;1(10):e86419.
6. 6. Feng S, Bucuvalas J. Tolerance After Liver Transplantation: Where Are We? Liver Transpl. 2017 Dec;23(12):1601-1614.
7. 7. Zhang CX, Wen PH, Sun YL. Withdrawal of immunosuppression in liver transplantation and the mechanism of tolerance Hepatobiliary Pancreat Dis Int. 2015 Oct;14(5):470-6.
8. 8. Minnie M Sarwal Review Clin Biochem.. Fingerprints of Transplant Tolerance Suggest Opportunities for Immunosuppression Minimization 2016 Mar;49(4-5):404-10

9. 9. Thomas E. Starzl, A.J.D., Noriko Murase, Massimo Trucco, Angus W.Thomson, Abdul S. Rao, and John J. Fung, Chimerism after organ transplantation. Curr Opin Nephrol Hypertens, 1997. 6(3): p. 292–298.
10. 10. Starzl TE , A.J.D., Trucco M, Murase N, Ricordi C, Ildstad S, Ramos H.Cell Migration and Chimerism After Whole-organ Transplantation:The Basis of Graft Acceptance. Hepatoloy, 1993. 17(6): p. 1127–1152.
11. 11. Starzl TE, A.J.D, Trucco M, Zeevi A, Ramos H, Terasaki P.Chimerism and Donor-specific non reactivity 27 to 29 years after kidney allotransplantation. Transplantation, 1993. 55(6): p. 1272–1277.
12. 12. Stephen I, Alexander, M.B., B.., Neil Smith, M.B., B.S., Min Hu, M.D., M.Med., et al, Chimerism and Tolerance in a Recipient of a Deceased-Donor Liver Transplant. NEJM, 2008. 358: p. 369-74.
13. 13. Mazariegos GV. Marino IR, Demetris AJ, Flynn B, Irish W, Michael JM, John J. Weaning of immunosuppression in liver transplant recipients. Transplantation, 1997. 27(63): p. 243-249.
14. 14 . Tryphonopoulos, P.Weppler D, Nishida S, Levi DM, Moon J, Tekin A. Madeline Velez, Danielle Rachel Neuman, Eddie Island, Gennaro Selvaggi, and Andreas G. Tzakis, Long-Term Follow-Up of 23 Operational Tolerant LiverTransplant Recipients. Transplantation, 2010. 90: p. 1556-1561.
15. 15. Tryphonopoulos P, Ruiz P, Weppler D, Nishida S, Levi DM, Moon J. Long-term follow-up of 23 operational tolerant liver transplant recipients. Transplantation. 2010 Dec 27;90(12):1556-61.
16. 16. Jain A, Mazariegos G, Pokharna R, Parizhskaya M, Kashyap R, Kosmach-Park B. The Absence of Chronic Rejection in Pediatric Primary Liver Transplant Patients Who Are Maintained on Tacrolimus-Based Immunosuppression: A Long-Term Analysis Transplantation. 2003 Apr 15;75(7):1020-5.
17. 17. Pilat N, W.T, Transplantation tolerance through mixed chimerism. Nat Rev Nephrol, 2010. 6(10): p. 594-605.
18. 18. Kinsella FAM, Zuo J, Inman CF, Pearce H, Maggs L, Eldershaw SE.Mixed chimerism established by hematopoietic stem cell transplantation is maintained by host and donor T regulatory cells. Blood Adv. 2019 Mar 12;3(5):734-743.
19. 19. Rickert CG, Markmann JF. Current state of organ transplant tolerance. Curr Opin Organ Transplant. 2019 Aug;24(4):441-450.
20. 20. Bishop GA, P., Bertolino PD, David G. Bowen, Geoffrey W. McCaughan. Tolerance in liver transplantation. Best Practice & Research Clinical Gastroenterology, 2012. 26: p. 73-84.
21. 21. Szabolcs P, W.J.B,. Thomson AV, Tolerance after solid organ and hematopoietic cell transplantation. Biol Blood Marrow Transplant, 2012. 18: p. 193-200.
22. 22. Harmon C, Sanchez-Fueyo A, O'Farrelly C, Houlihan DD. Natural Killer Cells and Liver Transplantation: Orchestrators of Rejection or Tolerance? Am J Transplant. 2016 Mar;16(3):751-7.
23. 23. Abrol N, Jadlowiec CC, Taner T. Revisiting the liver's role in transplant alloimmunity. World J Gastroenterol. 2019 Jul 7;25(25):3123-3135.