Prevention and Reversal of Lupus in NZB/NZW Mice by Transplantation of Purified Allogeneic Hematopoietic Stem Cells (HSC) with Non-Myeloablative Conditioning (NMT).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3198-3198
Author(s):  
Stephanie Smith-Berdan ◽  
Daphne Gille ◽  
Julie L. Christensen
Keyword(s):  
Lupus Erythematosus ◽  
Matched Control ◽  
Mixed Chimerism ◽  
Final Time ◽  
Myeloablative Conditioning ◽  
Hematopoietic Stem ◽  
Living Well ◽  
Nuclear Antigens ◽  
Final Time Point ◽  
Antibodies To Dsdna

Abstract Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease. Patients’ refractory to therapy may be considered for hematopoietic stem cell transplantation. Using lupus prone female NZB x NZW (NZBW) mice, we tested the ability of highly enriched, allogeneic HSC to prevent and reverse autoimmune symptoms with FACS purified haplo-identical allogeneic HSC. Ablative conditioning: 92 animals were given lethal TBI (14.5 Gy) and divided among 4 groups (Table 1). Urine and serology tested monthly, final time point before death tabulated. Transplantation with either syngeneic HSC or WBM accelerated disease in these mice, resulting in a rate of death exceeding age matched controls. Allogeneic transplanted mice had significantly greater survival above all groups (p= 0.0243). Proteinuria, elevated levels of circulating immune complexes (CIC), and auto-antibodies to dsDNA, nuclear antigens (ANA) and histones were lower in allo-HSC animals compared to the other ablative conditioning groups (p≤ 0.0001). Overall survival (OS) in allo-HSC animals was still unexceptional, possibly due to regimen related toxicity (TRM). Table 1: Ablative age@TX=75 days Age Matched Control Syngeneic WBM Syngeneic HSC Allogeneic HSC N 15 21 28 28 OS@420 days of age 20% 0% 0% 53% Proteinuria 100% 74% 75% 15% CIC 93% 81% 100% 25% Anti-dsDNA 100% 91% 100% 39% Anti-ANA 100% 86% 93% 39% Anti-Histone 93% 91% 100% 46% NMT conditioning: To determine if we could attenuate disease in NZBW mice already progressing into lupus-like disease with transplantation of allogeneic, purified HSC and reduce TRM, we developed a non-myeloablative conditioning protocol (2x5 Gy TBI + ATG + a-ASIALO-GM1) achieving an average mixed chimerism of 50%. Animals were treated at ~241 days with established symptoms of lupus (Table 2). While the group receiving conditioning alone, had a slight survival advantage over age matched control mice, the transplanted mice had greatly increased OS with 70% living well beyond 500 days of age (>250 days from transplant). Allo-HSC mice showed reversal or stabilization of their lupus symptoms including proteinuria, CIC, dsDNA and histone. Table 2: NMT age@Tx=241 days Age Matched Control Allogeneic HSC Conditioned Only N 10 33 30 OS@500 days of age 0% 70% 0% Proteinuria@Tx 20% 49% 47% Final Proteinuria 100% 39% 67% CIC 67% 50% 74% Anti-dsDNA 85% 15% 44% Anti-Histone 100% 37% 66% Conclusions: Ablative and NMT transplant can treat lupus; OS after NMT exceeds ablative conditioning; Induction of mixed chimerism with purified allogeneic HSC using NMT conditioning treats established lupus. The ability of pure HSC transplant and establishment of durable mixed chimerism to reverse established lupus makes it a reasonable strategy to test in man.

Reversal of autoimmune disease in lupus-prone New Zealand black/New Zealand white mice by nonmyeloablative transplantation of purified allogeneic hematopoietic stem cells

Blood ◽  
2007 ◽  
Vol 110 (4) ◽  
pp. 1370-1378 ◽  
Author(s):  
Stephanie Smith-Berdan ◽  
Daphne Gille ◽  
Irving L. Weissman ◽  
Julie L. Christensen
Keyword(s):  
New Zealand ◽  
Lupus Erythematosus ◽  
Immune Complexes ◽  
Circulating Immune Complexes ◽  
Mixed Chimerism ◽  
Hematopoietic Stem ◽  
Complete Replacement ◽  
Nuclear Antigens ◽  
Autoimmune Pathology ◽  
Mhc Haplotype

Abstract Patients with severe systemic lupus erythematosus (SLE) refractory to conventional treatment are candidates for autologous hematopoietic stem cell (HSC) transplantation if the intent is to reset the immunologic clock. These patients might be candidates for allotransplantation with (SLE)-resistant major histocompatibility complex (MHC) haplotype-matched HSC if partial or complete replacement of an autoimmune-prone system is the intent. Using lupus-prone New Zealand black × New Zealand white (NZBW) mice, we investigated the use of highly enriched, haplomismatched, allogeneic HSC to prevent development of or to treat established autoimmune pathology. Young NZBW mice receiving purified allogeneic HSC transplants had improved survival, decreased proteinuria, circulating immune complexes, and autoantibodies to nuclear antigens than did untreated mice or mice given NZBW HSCs. NZBW mice with established lupus-like disease that received nonmyeloablative conditioning and transplants of (MHC) haplomismatched allogeneic HSCs also had greatly increased overall survival. Mice that received transplants exhibited stabilization or reversal of their lupus symptoms; stabilized or decreased proteinuria, and a lower frequency of elevated circulating immune complexes or autoantibodies than did control mice. Induction of durable mixed chimerism by transplantation of purified allogeneic HSCs after nonmyeloablative conditioning has the potential to reverse symptoms of established NZBW lupus.

Durable Engraftment of Purified Allogeneic Hematopoietic Stem Cells Following Non-Myeloablative Conditioning.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2204-2204
Author(s):  
Mary-Elizabeth A. Muchmore ◽  
Matthew J. Burge ◽  
Judith A. Shizuru
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Low Dose ◽  
Conditioning Regimen ◽  
Mixed Chimerism ◽  
Host Immune System ◽  
Solid Organ ◽  
Myeloablative Conditioning ◽  
Hematopoietic Stem ◽  
Hsc Transplantation

Abstract Transplantation of purified allogeneic hematopoietic stem cells (HSC) has the potential to be a curative treatment for autoimmune diseases. Before it becomes a viable therapy, however, the treatment-related mortality and difficulty of achieving engraftment must be addressed. Our research has focused on developing non-myeloablative regimens that lead to donor-derived engraftment of purified HSC in a murine model. Total lymphoid irradiation (TLI) consists of low-dose fractionated irradiation targeted to the thymus, abdomen, and peripheral nodes, while the skull, lungs, and long bones remain shielded. The non-myeloablative conditioning regimen of TLI and anti-thymocyte globulin (ATG) was followed by HSC transplantation. HSCs were isolated by the composite phenotype of Thy1.1+, c-kit+, Sca-1+, and lineage- (KTLS) or, in strains lacking the Thy1.1 marker, c-kit+, Sca-1+, and lineage- (KSL). We tested HSC transplantations across three major histocompatiblity complex (MHC)-matched strain combinations known through previous studies in our group to have significantly different barriers to engraftment. In all three strain combinations we observed stable mixed chimerism (approximately 50% donor-derived cells) when high doses of HSC (10,000/mouse) were administered. Chimerism was measured at thirty-day intervals, and initially sharply increased and then stabilized around day ninety post-transplantation. In prior studies from our laboratory in a spontaneously arising autoimmune diabetes model, we demonstrated that mixed allogeneic chimerism alone following low dose total body irradiation (TBI) and HSC transplantation was sufficient to block the autoimmune pathogenesis. In order to establish a second clinically relevant conditioning regimen, we attempted here to lower the dose of TBI by using cyclophosphamide and ATG in addition to low dose TBI. However, less robust engraftment was observed as compared to the TLI/ATG approach. To study how TLI/ATG allows engraftment, we have examined the marrow of TLI/ATG conditioned, untransplanted animals. Though TUNEL and Caspase-3 assays did not show a significant increase in apoptosis compared to controls, a 71% decrease in the quantitative number of HSCs isolated from these animals was observed. This depletion of HSCs in the marrow could provide a niche for donor HSCs to inhabit. Further histologic studies on lymphoid organs exposed to radiation through TLI, including the thymus and spleen, are ongoing and may further elucidate the mechanisms by which TLI reconditions the host immune system. The durable mixed chimerism observed following TLI/ATG conditioning and HCT will be applied to mice affected with the rodent form of multiple sclerosis (experimental autoimmune encephalomyelitis) and to tolerance induction of solid-organ grafts. SUMMARY: The combination of TLI/ATG non-myeloablative conditioning and transplantation of allogeneic HSC leads to a durable mixed chimeric state between donor and host and will next be applied to the induction of tolerance to autoantigens and alloantigens.

scholarly journals Low-Dose Decitabine Monotherapy Reverses Mixed Chimerism in Adult Patients After Allogeneic Hematopoietic Stem Cell Transplantation With Myeloablative Conditioning Regimen: A Pilot Phase II Study

2021 ◽  
Vol 8 ◽  
Author(s):  
Ling Wang ◽  
Li-ning Wang ◽  
Ji-fang Zhou ◽  
Wen-hui Gao ◽  
Chuan-he Jiang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Graft Failure ◽  
Immune Modulation ◽  
Low Dose ◽  
Mixed Chimerism ◽  
Myeloablative Conditioning ◽  
Hematopoietic Stem ◽  
Donor Chimerism

T cell mixed chimerism (MC) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with myeloablative conditioning for hematological malignancies may indicate engraftment failure or disease relapse. Immune modulation, such as donor lymphocyte infusion (DLI) or the rapid tapering-off or stopping of immunosuppressive treatment, can reverse MC to full donor chimerism (FDC). However, the development or aggravation of graft-versus-host disease (GvHD) and the related mortality remain major concerns with immune modulation. In this prospective, single-arm study (NCT03663751), we tested the efficacy and safety of low-dose decitabine (LD-DAC, 5 mg/m2 daily for 5 days and repeated every 6–8 weeks) without immune modulation in the treatment of patients with MC to prevent MC-associated relapse and/or graft failure. A total of 14 patients were enrolled. All the patients received myeloablative conditioning regimens, and MC was documented from day +30 to day +180 after allo-HSCT with a donor chimerism level ranging from 59 to 97% without detectable measurable residual disease (MRD). Eleven patients (78.6%) responded favorably to treatment, showing increased levels of donor chimerism (≥95%), while nine achieved FDC. All of these patients maintained their responses for a median of 11 months (3–22). The three patients who failed to respond favorably eventually either relapsed or experienced graft failure. All three were alive and in remission at the last follow-up after the second allo-HSCT. LD-DAC monotherapy was well tolerated and exerted limited hematological and nonhematological toxicities. New-onset GvHD symptoms were observed only in two patients. Overall, the estimated 2-year overall survival (OS) and event-free survival (EFS) after allo-HSCT were 90.9 ± 8.7% and 67.0 ± 13.7%, respectively. In conclusion, LD-DAC alone could reverse MC in most patients after allo-HSCT with myeloablative conditioning, while those who achieved FDC enjoyed long-term EFS without major complications. Further prospective studies with larger sample sizes are warranted to confirm the benefits of LD-DAC.

Interactions Between Donor CD4 Cells and Residual Host Cells After Nonmyeloablative Hematopoietic Stem Cell Transplantation Suppress Hematopoiesis and Lead to Graft Rejection

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 75-75 ◽  
Author(s):  
Antonia MS Mueller ◽  
Mareike Florek ◽  
Husein Hadeiba ◽  
Judith A Shizuru
Keyword(s):  
Cell Transplantation ◽  
Graft Rejection ◽  
Hematopoietic Cell Transplantation ◽  
Cytokine Production ◽  
Conflicts Of Interest ◽  
Annexin V ◽  
Host Cells ◽  
Mixed Chimerism ◽  
Myeloablative Conditioning ◽  
Hematopoietic Stem

Abstract Abstract 75 While non-myeloablative conditioning significantly reduces morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT), the risk of graft rejection increases, because persistent host cells mediate host-vs-graft reactivity. Here we studied the dynamics of engraftment and hematopoietic reconstitution after non-myeloablative radiation (XRT) in a minor antigen-mismatched model with high barriers to engraftment. BALB.K mice received purified hematopoietic stem cells (HSC: cKit+Thy1.1loSca1+Lin−) +/− TC from AKR/J donors. Recipients of pure HSC or HSC+CD8 TC regularly achieved stable mixed chimerism; however, if grafts contained CD4+CD25− TC (CD4con), recipients failed to engraft. This lack of engraftment was associated with BM hypocellularity (median 3.8 vs 13.3 x10^6 cells/2 legs in HSC+CD4con vs HSC recipients, respectively; p=0.0003), and lymphopenia (<5% vs >40%) at 2 weeks (w) post-HCT. In addition, 2w post-HCT the BM of mice given HSC+CD4con contained increased proportions of CD4 TC which expressed high levels of IFNγ (median 45% of donor vs. 13% of host CD4 TC; p<.001) that exceeded the levels of IFNγ present their spleens or in the BM of control groups (HSC only, wild type [WT], or XRT <10%). A primary determinant of naïve TC immunoreactivity is antigen presentation by dendritic cells (DC). Plasmacytoid DC (CD11c+B220+), which have tolerogenic activity, dominated the BM DC pool in mice given pure HSC at 1–2w post-HCT, but were lacking in recipients of HSC+CD4con. In this latter group, primarily myeloid DC (CD11c+Mac1+) were present that strongly expressed MHCII, CD40, and CD80. This inflammatory profile of myeloid DC was more pronounced in the BM than in the spleens of HSC+CD4con recipients, and IL-12 secretion was measurable in the myeloid DC of these recipients, even without the external endotoxin stimulation which is usually required to detect cytokine production. The IL-12/IFNγ axis is reported to be important in autoimmune pathologies and acute graft rejection of solid organs. To elucidate the mechanism by which IFNγ producing donor CD4 TC suppress engraftment and lymphopoiesis in our system, the progenitor pool in the BM of HSC+/−CD4con recipients was analyzed at 1–2w post-HCT. As expected, the BM recipients of purified HSC had all maturation stages of stem and progenitor cells (HSC: cKit+Sca1+Lin−Flt3−CD34−CD150+ [LT=long-term]/CD150− [ST=short term]; multipotent progenitors, MPP: cKit+Sca1+Lin−Flt3+/−CD34+/−). In contrast, mice given HSC+CD4con lacked MPP, while their population of ST (>LT) HSC was enlarged. These HSC were not apoptotic (as assessed by annexin V staining), but were cell cycle arrested (assessed by DNA content analysis). To study the functionality of these HSC outside the inflammatory environment, LT+ST HSC from HSC+CD4con recipients were FACS purified at 2w post-HCT and infused into secondary Rag2γc-/- recipients. These adoptively transferred HSC and promptly sustained multilineage hematopoiesis derived from the primary BALB.k host. Our results suggest that interactions between naïve donor CD4 TC and immunocompetent residual host cells, such as DC, create a pro-inflammatory environment involving the IL-12/IFNγ axis. We evaluated several other MHC-identical strain combinations which demonstrated lower levels of cytokine production with improved hematopoiesis compared to the AKR into BALK.K combination. These differences imply that impaired hematopoiesis is due to activation of donor CD4 TC in response to disparate minor alloantigens, and not due to non-specific inflammation. Such immune reactions appear to prevent engraftment of donor HSC and also inhibit the HSC expansion required to restore hematopoiesis early post-HCT. We conclude that HCT with pure HSC can result in superior immune reconstitution and donor chimerism after non-myeloablative conditioning. Pure HSC are immunologically anergic, and do not trigger inflammation in the BM microenvironment. As it is generally believed that TC augment donor HSC engraftment, our results are of broad significance because they reveal critical interactions between donor and host populations after non-myeloablative conditioning. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Autoimmune Complications in Hematologic Neoplasms

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1532
Author(s):  
Wilma Barcellini ◽  
Juri Alessandro Giannotta ◽  
Bruno Fattizzo
Keyword(s):  
Lupus Erythematosus ◽  
Checkpoint Inhibitors ◽  
Myeloproliferative Neoplasms ◽  
Pure Red Cell Aplasia ◽  
Lymphocytic Leukemia ◽  
Cell Transplant ◽  
Acute Leukemias ◽  
Hematopoietic Stem ◽  
Non Hodgkin Lymphoma ◽  
Diagnostic Difficulties

Autoimmune cytopenias (AICy) and autoimmune diseases (AID) can complicate both lymphoid and myeloid neoplasms, and often represent a diagnostic and therapeutic challenge. While autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP) are well known, other rarer AICy (autoimmune neutropenia, aplastic anemia, and pure red cell aplasia) and AID (systemic lupus erythematosus, rheumatoid arthritis, vasculitis, thyroiditis, and others) are poorly recognized. This review analyses the available literature of the last 30 years regarding the occurrence of AICy/AID in different onco-hematologic conditions. The latter include chronic lymphocytic leukemia (CLL), lymphomas, multiple myeloma, myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), myeloproliferative neoplasms, and acute leukemias. On the whole, AICy are observed in up to 10% of CLL and with higher frequencies in certain subtypes of non-Hodgkin lymphoma, whilst they occur in less than 1% of low-risk MDS and CMML. AID are described in up to 30% of myeloid and lymphoid patients, including immune-mediated hemostatic disorders (acquired hemophilia, thrombotic thrombocytopenic purpura, and anti-phospholipid syndrome) that may be severe and fatal. Additionally, AICy/AID are found in about 10% of patients receiving hematopoietic stem cell transplant or treatment with new checkpoint inhibitors. Besides the diagnostic difficulties, these AICy/AID may complicate the clinical management of already immunocompromised patients.

Stem cell transplantation: progress in Asia

Lupus ◽  
2010 ◽  
Vol 19 (12) ◽  
pp. 1468-1473 ◽  
Author(s):  
L. Sun
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Lupus Erythematosus ◽  
Systemic Lupus ◽  
Hematopoietic Stem ◽  
The Past ◽  
Complex Autoimmune Disease ◽  
Significant Mortality

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with multiorgan involvement and high mortality, which was reduced because of the most widely and classically used immunosuppressive therapies. However, some patients continue to have significant mortality. So a shift in the approach to the treatment of SLE is needed. In the past decade, most transplants have been performed in the treatment of SLE with allogeneic or autologous hematopoietic stem cells and currently emerging mesenchymal stem cells. There are some important differences between the two procedures.

Systemic Lupus Erythematosus

2019 ◽  
Author(s):  
Kyriakos A. Kirou ◽  
Michael D. Lockshin
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Sun Exposure ◽  
Disease Classification ◽  
Discoid Lupus Erythematosus ◽  
Neurologic Disease ◽  
Systemic Lupus ◽  
Nuclear Antigens ◽  
Key Words Systemic Lupus

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune illness characterized by autoantibodies directed at nuclear antigens that cause clinical and laboratory abnormalities, such as rash, arthritis, leukopenia and thrombocytopenia, alopecia, fever, nephritis, and neurologic disease. Most or all of the symptoms of acute lupus are attributable to immunologic attack on the affected organs. Many complications of long-term disease are attributable to both the disease and its treatment. Intense sun exposure, drug reactions, and infections are circumstances that induce flare; the aim of treatment is to induce remission. This chapter is divided into sections dealing with SLE’s definitions; epidemiology; pathogenesis; disease classification, diagnosis, and differential diagnosis; and treatment. This review contains 10 figures, 12 tables, and 97 references. Key Words: Systemic lupus erythematosus, Dermatomyositis, Sjögren syndrome, rheumatoid arthritis, systemic sclerosis, Discoid lupus erythematosus, truncal psoriasiform, annular polycyclic rash

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