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Transplantation Tolerance, Microchimerism, and the Two-Way Paradigm
Published in Thomas F. Kresina, Immune Modulating Agents, 2020
Thomas E. Starzl, Anthony J. Demetris, Noriko Murase, Massimo Trucco, Angus W. Thomson, Abdul S. Rao, John J. Fung
Thus, immunosuppressive agents, which have diverse sites of action [152], do not cause tolerance, but rather permit it with variable success by allowing an alternative normal function of the immune system to be expressed. Chimerism and the derivative state of tolerance are almost contemporaneous in numerous rodent models of liver transplantation (Figure 6). In contrast, the cause (chimerism) and the effect (tolerance) are separated by months or years when liver transplantation is performed in outbred animals and humans (Figure 6), no matter what the means of immunosuppression. In many cases, the desired drug-free end point may never be reached. Chimerism (and its companion allograft) can nevertheless be maintained for the lifetime of such patients under continuous immunosuppression.
Allogeneic Hematopoietic Cell Transplantation After Nonmyeloablative Conditioning
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Frédéric Baron, Frederick R. Appelbaum, Brenda M. Sandmaier
The engraftment kinetics after nonmyeloablative conditioning regimen were first analyzed by Childs et al. (17). The authors studied chimerism (i.e., proportion of hematopoietic cells of donor origin) evolution in 15 patients conditioned with fludarabine (125 mg/m2) and cyclophosphamide (120 mg/kg). The patterns of engraftment varied between patients, but most often, full donor chimerism was achieved earlier among T-cells than among granulocytes, and achievement of full donor T-cell chimerism preceded GVHD and antitumor responses. Conversely, Ueno et al. studied chimerism evolution in 23 patients with metastatic tumors transplanted after conditioning with fludarabine (125–150 mg/m2) and melphalan (140 mg/m2) (26). All patients had full donor T-cell and granulocyte chimerisms by day 30 after HCT.
Variation of sex differentiation
Published in Joseph S. Sanfilippo, Eduardo Lara-Torre, Veronica Gomez-Lobo, Sanfilippo's Textbook of Pediatric and Adolescent GynecologySecond Edition, 2019
Anne-Marie Amies Oelschlager, Margarett Shnorhavorian
Classification of DSD conditions is based on underlying karyotype, including 46,XX DSD; 46,XY DSD; and sex chromosome DSD. In general, ambiguous genitalia in infancy with 46,XX DSD conditions are due to excess virilization, and 46,XY DSD conditions are due to undervirilization. Sex chromosome disorders include gonadal dysgenesis; Turner syndrome (45,X); mixed gonadal dysgenesis (45,X/46,XY); Klinefelter's syndrome and variants (47,XXY); and ovotesticular DSD (45,X/46,XY or 46,XX/46,XY). Additional genetic etiologies include mosaicism and chimerism. The causes of DSD can be broadly categorized as sex steroid excess or deficiency due to a central or peripheral etiology, hormonal receptor deficiencies, or atypical or slowed migration of the Müllerian or wolffian ducts (Tables 7.2 and 7.3).
Post-transplant CD34+ selected stem cell boost as an intervention for declining mixed chimerism following reduced intensity conditioning allogeneic stem cell transplant in children and young adults with sickle cell disease: A case series
Published in Pediatric Hematology and Oncology, 2022
Alexander Ngwube, Cara Franay, Niketa Shah
Mixed chimerism and eventual graft loss occurs in a proportion of children with sickle cell disease (SCD) who receive a reduced-intensity conditioning (RIC) regimen for allogeneic hematopoietic stem cell transplantation (HSCT).1 Currently, there is no established standard-of-care therapy for mixed chimerism, although different strategies have been used. Stable mixed chimerism is fully acceptable. In myeloablated or immunoablated recipients, declining chimerism prompts immune suppression withdrawal, however in low intensity regimens recipients, continuing immune suppression has been effective.2 A gradual decline may be salvageable with immune suppression adjustments, but a rapid decline in chimerism is difficult to halt and usually requires a second stem cell infusion after reconditioning. Donor lymphocyte infusions (DLI) are generally not beneficial and can induce unwanted graft versus host disease (GVHD)2,3 and hence should be avoided in this patient population. However, the ability to infuse products such as CD34+ selected stem cells may be valuable in RIC to avert the risk of GVHD.
Use of chimerism analysis after allogeneic stem cell transplantation: Belgian guidelines and review of the current literature
Published in Acta Clinica Belgica, 2021
Anke Delie, Anke Verlinden, Karolien Beel, Dries Deeren, Dominiek Mazure, Frédéric Baron, Dimitri Breems, Ann De Becker, Carlos Graux, Philippe Lewalle, Johan Maertens, Xavier Poire, Helene Schoemans, Dominik Selleslag, Florence Van Obbergh, Tessa Kerre
Chimerism analysis can be performed on unfractionated peripheral blood cells, bone marrow or isolated cell lineages. A patient can either have a complete chimerism (CC), when the % of donor origin cells exceeds the upper detection limit of the analysis used (usually corresponding with donor chimerism of >95-99.9% depending on the sensitivity of the used test cfr. infra), or a mixed chimerism (MC) where donor and recipient hematopoietic cells coexist. However, the state of a patient’s chimerism is subject to change over time and a patient can present with an increasing or decreasing donor chimerism, i.e. an increasing or decreasing amount of donor hematopoiesis compared to previous analysis. Lastly, levels of chimerism are not necessarily the same between different cell populations and patients can present with a split chimerism, where CC has been achieved in one or more cell lineages but MC still exists in other cell lineages [1–5]. (Table 1)
Busulfan-based reduced toxicity conditioning regimen used in hematopoietic stem cell transplantation in HLH patients results in sustained donor chimerism
Published in Pediatric Hematology and Oncology, 2021
Erin Goode, Holly Miller, Dana Salzberg, Courtney Campbell, Kristen Beebe, Charlotte Schwalbach, Roberta H. Adams, Alexander Ngwube
Donor chimerism was established by using short tandem repeats for allele DNA sequencing. Longitudinal data of chimerism were available for all patients. We defined full chimerism as the presence of ≥90% donor cells, whereas mixed chimerism reflected as a percentage of donor cells ranging between 20% and 89% and graft failure was a percentage of donor cells <20%.12 For patients demonstrating mixed chimerism, institutional standard practice is to start withdrawing immunosuppressant therapy with donor chimerism of <90%. Immunosuppressant therapy is weaned by 20% weekly, and changes to donor chimerism are evaluated closely. If the patient is quickly losing the graft, then the withdrawal of immunosuppressant therapy is quickened over less than 2 weeks. The event-free survival, defined as engraftment failure, rejection, or death due to any cause, and overall survival was calculated using the Kaplan-Meier estimators.