tacrolimus and Immunologic-Deficiency-Syndromes

Myelodysplastic syndrome (MDS) in children is often associated with chromosomal anomalies and trisomy 8 is a characteristic karyotypic feature in up to 20% of the cases. Behçet disease is a rare multisystem inflammatory disorder characterized by recurrent mouth and genital ulcers. MDS with trisomy 8 has been observed in adult patients with Behçet syndrome with some cases developing prior to the clinical manifestations of the latter. We present a female with a similar association and explain the importance of identifying the coexisting conditions. The immunological abnormalities, which may be observed in MDS and their possible mechanisms, are also discussed.

Topics: Adolescent; Anemia, Refractory; Behcet Syndrome; Chromosomes, Human, Pair 8; Female; Humans; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Karyotyping; Oral Ulcer; Tacrolimus; Thalidomide; Trisomy

Topics: Azathioprine; Cyclophosphamide; Cyclosporine; Diagnosis, Differential; Humans; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Methotrexate; Opportunistic Infections; Prednisolone; Prognosis; Tacrolimus

We treated 14 patients with GATA2 deficiency using a nonmyeloablative allogeneic hematopoietic stem cell transplantation regimen. Four patients received peripheral blood stem cells from matched related donors (MRD), 4 patients received peripheral blood stem cells from matched unrelated donors (URD), 4 patients received hematopoietic stem cells from umbilical cord blood donors (UCB), and 2 patients received bone marrow cells from haploidentical related donors. MRD and URD recipients received conditioning with 3 days of fludarabine and 200 cGy total body irradiation (TBI). Haploidentical related donor recipients and UCB recipients received cyclophosphamide and 2 additional days of fludarabine along with 200 cGY TBI. MRD, URD, and UCB recipients received tacrolimus and sirolimus for post-transplantation immunosuppression, whereas haploidentical recipients received high-dose cyclophosphamide followed by tacrolimus and mycophenolate mofetil. Eight patients are alive with reconstitution of the severely deficient monocyte, B cell, and natural killer cell populations and reversal of the clinical phenotype at a median follow-up of 3.5 years. Two patients (1 URD recipient and 1 UCB recipient) rejected the donor graft and 1 MRD recipient relapsed with myelodysplastic syndrome after transplantation. We are currently using a high-dose conditioning regimen with busulfan and fludarabine in patients with GATA2 deficiency to achieve more consistent engraftment and eradication of the malignant myeloid clones.

Topics: Adolescent; Adult; Allografts; Antineoplastic Agents; Bone Marrow Transplantation; Child; Cord Blood Stem Cell Transplantation; Female; Follow-Up Studies; GATA2 Transcription Factor; Genetic Diseases, Inborn; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Male; Middle Aged; Sirolimus; Tacrolimus; Transplantation Conditioning; Unrelated Donors; Vidarabine; Whole-Body Irradiation

In this study, our aim was to compare the outcomes of everolimus versus mycophenolate mofetil plus standard-dose tacrolimus immunosuppression in patients who received de novo kidney transplant at our center in Fukuoka, Japan.. In this retrospective, observational, single-center, inverse probability of treatment weighting analysis study, 225 recipients who underwent kidney transplant at our center between January 2013 and December 2018 were included. The variables considered were recipient age/sex, duration of dialysis, cytomegalovirus mismatch (seronegative recipient and seropositive donor), cause of end-stage renal disease, donor age/sex, and number of HLA mismatches.. Our analyses included 85 transplant recipients in the everolimus group and 141 transplant recipients in the mycophenolate mofetil group (n = 226 overall). There were no significant differences between the groups at 1 year for incidence of patient death and allograft loss, biopsy-proven acute rejection, BK virus-associated nephropathy, surgical complications, delayed graft function, and posttransplant diabetes mellitus. Incidence of cytomegalovirus infection and estimated glomerular filtration rate were significantly lower in the everolimus group than in the mycophenolate mofetil group. Posttransplant triglyceride and low-density lipoprotein were higher in the everolimus group than in the mycophenolate mofetil group. Multivariate ordered logistic analysis showed that older donor age and an acute rejection episode, but not induction with everolimus or mean tacrolimus trough concentration throughoutthe firstpostoperative year,were significant risk factors for severity of interstitial fibrosis/tubular atrophy at the 1-year protocol biopsy (P = .004 and P < .001,respectively).. Short-term outcomes with everolimus plus standard-dose tacrolimus in recipients of de novo kidney transplant were comparable to those with mycophenolate mofetil plus standard-dose tacrolimus.

Topics: Everolimus; Female; Graft Rejection; Humans; Immunologic Deficiency Syndromes; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Male; Mycophenolic Acid; Retrospective Studies; Tacrolimus; Treatment Outcome

Other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPDs) occur in patients receiving immunosuppressive drugs for autoimmune diseases; however, their clinicopathological and genetic features remain unknown. In the present study, we analysed 67 patients with OIIA-LPDs, including 36 with diffuse large B-cell lymphoma (DLBCL)-type and 19 with Hodgkin lymphoma (HL)-type. After discontinuation of immunosuppressive drugs, regression without relapse was achieved in 22 of 58 patients. Spontaneous regression was associated with Epstein-Barr virus positivity in DLBCL-type (P = 0·013). The 2-year overall survival and progression-free survival (PFS) at a median follow-up of 32·4 months were 92·7% and 72·1% respectively. Furthermore, a significant difference in the 2-year PFS was seen between patients with DLBCL-type and HL-type OIIA-LPDs (81·0% vs. 40·9% respectively, P = 0·021). In targeted sequencing of 47 genes in tumour-derived DNA from 20 DLBCL-type OIIA-LPD samples, histone-lysine N-methyltransferase 2D (KMT2D; eight, 40%) and tumour necrosis factor receptor superfamily member 14 (TNFRSF14; six, 30%) were the most frequently mutated genes. TNF alpha-induced protein 3 (TNFAIP3) mutations were present in four patients (20%) with DLBCL-type OIIA-LPD. Cases with DLBCL-type OIIA-LPD harbouring TNFAIP3 mutations had shorter PFS and required early initiation of first chemotherapy. There were no significant factors for spontaneous regression or response rates according to the presence of mutations. Overall, OIIA-LPDs, especially DLBCL-types, showed favourable prognoses.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Epstein-Barr Virus Infections; Female; Herpesvirus 4, Human; Histone-Lysine N-Methyltransferase; Hodgkin Disease; Humans; Iatrogenic Disease; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Kaplan-Meier Estimate; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Male; Methotrexate; Middle Aged; Myeloid-Lymphoid Leukemia Protein; Prognosis; Progression-Free Survival; Proportional Hazards Models; Receptors, Tumor Necrosis Factor, Member 14; Retrospective Studies; Rheumatic Diseases; Tacrolimus; Tumor Necrosis Factor alpha-Induced Protein 3

Allogeneic bone marrow transplantation (alloBMT) is the only cure for many primary immune deficiency disorders (PIDD), primary immune regulatory disorders (PIRD), and inherited bone marrow failure syndromes (IBMFS).. We report the results of 25 patients who underwent alloBMT using reduced intensity conditioning (RIC), alternative donors, and post-transplantation cyclophosphamide (PTCy). In an attempt to reduce regimen-related toxicities, we removed low-dose TBI from the prep and added mycophenolate mofetil and tacrolimus for graft-versus-host disease (GVHD) prophylaxis for all donor types in the latter 14 patients. Donors were haploidentical related (n = 14), matched unrelated (n = 9), or mismatched unrelated (n = 2). The median age was 9 years (range 5 months-21 years).. With a median follow-up of 26 months (range 7 months-9 years), the 2-year overall survival is 92%. There were two deaths, one from infection, and one from complications after a second myeloablative BMT. Three patients developed secondary graft failure, one at 2 years and two at >3 years, successfully treated with CD34 cell boost in one or second BMT in two. The remaining 20 patients have full or stable mixed donor chimerism and are disease-free. The incidence of mixed chimerism is increased since removing TBI from the prep. The 6-month cumulative incidence of grade II acute GVHD is 17%, with no grade III-IV. The 1-year cumulative incidence of chronic GVHD is 14%, with severe of 5%.. This alloBMT platform using alternative donors, RIC, and PTCy is associated with excellent rates of engraftment and low rates of GVHD and non-relapse mortality, and offers a curative option for patients with PIDD, PIRD, and IBMFS.. ClinicalTrials.gov Identifier: NCT04232085.

Topics: Adolescent; Adult; Bone Marrow Failure Disorders; Bone Marrow Transplantation; Child; Child, Preschool; Cyclophosphamide; Disease-Free Survival; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Deficiency Syndromes; Infant; Infant, Newborn; Male; Mycophenolic Acid; Tacrolimus; Tissue Donors; Transplantation Conditioning; Young Adult

CD72 is a B cell-specific glycoprotein that has been shown to be important for activation of mature B cells. Previously we showed that some of the early signaling events, such as calcium mobilization and phospholipase-gamma activation, were similar in B cell Ag receptor (BCR)- and CD72-stimulated B cells and that BCR- but not CD72-mediated early signaling events were blocked by protein kinase A activation. The present report shows that CD72 ligation induces a variety of tyrosine-phosphorylated proteins, most of which were of the same molecular mass as those seen in anti-IgM-treated B cells, except for a 72-kDa protein. Further analysis showed that the tyrosine kinases lyn and blk were activated in CD72-ligated B cells. Interestingly, the non-src kinase syk was not activated in CD72-stimulated cells whereas the tec family kinase btk was activated in both CD72- and BCR-stimulated B cells. Furthermore, B cells from xid mice were unresponsive to CD72-induced proliferation, indicating an essential role for btk in CD72-induced signaling events. Surprisingly, tyrosine phosphorylation of phospholipase C-gamma2 was normal in CD72-stimulated cells in spite of a lack of activation of syk. Furthermore, B cell proliferation through CD72 was blocked by the immunosuppressive agents cyclosporin A and FK506, indicating the important role for Ca2+-regulated activation events similar to BCR-stimulated cells. We propose that btk can substitute for syk in inducing phospholipase C-gamma2 tyrosine phosphorylation and initiating calcium mobilization in CD72-stimulated B lymphocytes.

Topics: Agammaglobulinaemia Tyrosine Kinase; Animals; Antigens, CD; Antigens, Differentiation, B-Lymphocyte; B-Lymphocyte Subsets; Cyclosporine; Enzyme Precursors; Female; Immune Tolerance; Immunologic Deficiency Syndromes; Intracellular Signaling Peptides and Proteins; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Mice, Inbred CBA; Mice, Inbred DBA; Mice, Mutant Strains; Phosphorylation; Protein-Tyrosine Kinases; src-Family Kinases; Substrate Specificity; Syk Kinase; Tacrolimus; Type C Phospholipases; Tyrosine; X Chromosome

An 8-month-old child with an immunodeficiency disorder characterized by abnormal lymphocyte function and by low IgG and IgA levels had combined liver and small bowel transplantation under tacrolimus and steroid immunosuppression for the treatment of short gut syndrome and hepatic cirrhosis. The patient developed an early postoperative episode of Pneumocystis carinii pneumonia, and a subsequent surgical complication, prompting discontinuance of tacrolimus. A skin rash eventually shown to be graft-versus-host disease (GVHD) developed in the flank on the 12th post-transplant day and gradually became generalized. Peritonitis, sepsis, multisystem organ failure including the liver allograft led to death on the 23rd post-operative day. The mechanisms leading to post-transplant GVHD under the specific circumstances in this case are discussed.

Topics: Exanthema; Fatal Outcome; Female; Glucocorticoids; Graft vs Host Disease; Humans; IgA Deficiency; IgG Deficiency; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Infant; Intestine, Small; Ischemia; Liver; Liver Cirrhosis; Liver Transplantation; Lymphocytes; Methylprednisolone; Multiple Organ Failure; Peritonitis; Pneumonia, Pneumocystis; Sepsis; Short Bowel Syndrome; Tacrolimus