Cyclophosphamide-Induced Immunological Tolerance: an Overview

doi:10.1016/S0171-2985(96)80033-7

Immunobiology

Volume 195, Issue 2, July 1996, Pages 129-139

https://doi.org/10.1016/S0171-2985(96)80033-7 Get rights and content

Abstract

A cyclophosphamide (CP)-induced tolerance system in mice that primarily consists of donor cell injection followed by CP-treatment was found useful for inducing a long-lasting allo- or xeno-tolerance to various solid organs. In the cells-followed-by-CP system, the sequential mechanisms of tolerance were clarified using the specific correlation between superantigens and certain T cell receptor (TCR) Vβ segments. Those include the clonal destruction of antigen-stimulated mature T cells, the peripheral clonal deletion associated with peripheral chimerism, the intrathymic clonal deletion associated with intrathymic chimerism, and the clonal anergy. The generation of suppressor T cells was another important mechanism of tolerance in the late stage. Special care was taken to overcome the «hard» barriers of allo- or xeno-combinations by reducing the «split tolerance» produced through the clonal destruction mechanism. For this purpose, the tolerogen, antimitotic drugs, their doses, timing, route of administration, combined immunosuppressants, and supportive treatment were all crucial for successful induction of a long-lasting skin tolerance. This system may be applicable to human transplantation.

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Haploidentical donor (haplo-) hematopoietic stem cell transplantation (HSCT) with post-transplantation cyclophosphamide (PTCy) is now performed on a large scale worldwide. Our patient outcomes did not completely reflect the results published by other groups. We herein present the results of 60 patients with hematologic malignancies treated homogeneously on a modified version of the standard protocol by adding ATG as an additional graft-versus-host disease (GVHD) prophylaxis measure. This was a retrospective analysis of 60 haplo-HSCT recipients using a myeloablative conditioning regimen with antithymocyte globulin and PTCy for GVHD prophylaxis. At 5 years, overall survival was 59.2%, relapse-free survival (RFS) was 48.6%, and chronic GVHD (cGVHD) and relapse-free survival was 40%. The median time to neutrophil and platelet engraftment was 16 days and 28.5 days, respectively. The rates of grade II-IV acute GVHD and extensive cGVHD were 46.7% and 23.3%, respectively. The cumulative incidence of relapse was 30%, nonrelapse mortality was 21.6%, and transplantation-related mortality was 11%. Higher Disease Risk Index and 50% HLA match were associated with lower RFS. Female donor to male recipient and older donor age were associated with an elevated risk of cGVHD. The use of PTCy might not yield the same results in different populations. Many remaining questions need to be addressed in randomized trials, including optimal graft source and donor, date of calcineurin inhibitor initiation, personalized or targeted dose of PTCy, immune reconstitution, and others.
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Tacrolimus (TAC) plus short-term methotrexate (stMTX) is used for graft-versus-host disease (GVHD) prophylaxis after allogeneic hematopoietic stem cell transplantation (allo-HSCT). TAC blood concentrations are frequently adjusted to enhance the graft-versus-leukemia/lymphoma effect or attenuate severe GVHD. Limited information is available on the clinical impact of these adjustments and the optimal time to perform them in order to achieve good clinical outcomes.
We retrospectively analyzed 211 patients who underwent allo-HSCT at our institutes.
Higher TAC concentrations in week 3 correlated with a significantly higher cumulative incidence of relapse (CIR) (P = 0.03) and lower nonrelapse mortality (P = 0.04). The clinical impact of high TAC concentrations in week 3 on CIR was detected in the refined disease risk index: low/intermediate (P = 0.04) and high (P < 0.01), and conditioning regimens other than cyclophosphamide/total body irradiation and busulfan/cyclophosphamide (P = 0.07). Higher TAC concentrations in week 1 correlated with a lower grade 2-4 acute GVHD rate (P = 0.01). Higher TAC concentrations in weeks 2 and 3 correlated with slightly lower (P = 0.05) and significantly lower (P = 0.02) grade 3-4 acute GVHD rates, respectively. Higher TAC concentrations in weeks 1 and 3 were beneficial for severe acute GVHD in patients with a human leukocyte antigen-matched donor (P = 0.03 and P < 0.01, respectively), not treated with anti-thymocyte globulin (P = 0.02 and P = 0.02, respectively), and receiving three stMTX doses (P = 0.03 and P = 0.02, respectively).
The clinical impact of TAC concentrations varied according to patient characteristics, including disease malignancy, conditioning regimens, donor sources, and GVHD prophylaxis. These results suggest that TAC management needs to be based on patient profiles.
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Lactobacillus (L.) casei NCU011054 isolated from infant feces has been proven to be a potential probiotic in vitro. The present study aimed to investigate the effects of L. casei NCU011054 on the immune response and gut microbiota in cyclophosphamide (CP)-induced immunosuppression mice. Results indicated that L. casei NCU011054 could increase the levels of mucin (Muc2) and tight junction proteins (ZO-1, occludin and claudin-1). Moreover, L. casei NCU011054 was found to upregulate TLRs/NF-κB pathway (TLR-2, TLR-4, TLR-6, p65 and NF-κB) and two transcription factors (T-bet and GATA-3) mRNA levels, and enhance the number of CD4⁺T cells. Th1-related cytokines (IL-12p70, IFN-γ and TNF-α) and Th2-related cytokines (IL-2, IL-4, IL-6 and IL-10) significantly increased after L. casei NCU011054 treatment. More importantly, L. casei NCU011054 increased the ratio of T-bet to GATA-3 and IFN-γ to IL-4. Apart from these, L. casei NCU011054 remodeled gut microbiota and modulated gut metabolites in CP-induced immunosuppressed mice. The correlation analysis showed that Lactobacillus upregulated by L. casei NCU011054 was positively correlated with TLRs/NF-κB pathway, and the ratio of T-bet to GATA-3 and IFN-γ to IL-4. All findings revealed that L. casei NCU011054 could improve intestinal immune dysfunction and modulate Th1/Th2 balance via TLRs/NF-κB pathway in CP-induced immunosuppressed mice.
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Graft-versus-host disease (GVHD) is a potentially fatal complication and is one of the most common causes of nonrelapse mortality after allogeneic hematopoietic cell transplantation. Some of the factors that determine the risk of GVHD include the degree of human leukocyte antigen matching, donor type, graft source, gender disparity, conditioning intensity, and the type of GVHD prophylaxis. GVHD comprises two distinct entities categorized as acute or chronic depending on specific manifestations. Common organs involved by acute GVHD are skin, gastrointestinal tract, and liver, and is characterized by skin rash, nausea, vomiting, secretory diarrhea, and cholestatic liver dysfunction. Chronic GVHD can affect virtually any organ, with the most common being eyes, mouth, skin, joint/fascia, gastrointestinal tract, liver, lungs, and genitalia. In this chapter, we discuss the epidemiology, risk factors, pathophysiology, various classification systems used for staging and grading, and clinical manifestations of acute and chronic GVHD. We then elaborate on GVHD prevention strategies and briefly describe the treatment of GVHD. Finally, we touch on novel approaches to prevent or treat GVHD and future directions.
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Citation Excerpt :
Importantly, no patient in these three studies experienced aGvHD or cGvHD [18,51,53,54]. Additionally, published studies confirmed that high-dose PTCy used for GvHD prophylaxis is selectively immuno-suppressive, but not myeloablative[55]. Previous studies with HCT in SCD have shown that MC provides sufficient production of donor-derived RBC with reversion of the SCD phenotype in the absence of GvHD[18,56].
For patients with high-risk sickle cell disease (SCD) without any available matched sibling or unrelated donor, haploidentical stem cell transplantation (haploHCT) expands the availability of this life-saving intervention to nearly all patients who may benefit from HCT. The greatest challenge in haploHCT has been the significant risk of graft failure. Developing a treatment modality which sustains engraftment without increasing the incidence of debilitating graft-versus-host disease (GvHD) remains the ultimate goal. A number of modifications have been explored to overcome the high incidence of graft rejection and severe GvHD including: (1) ex-vivo T-cell depletion (via CD34⁺ selection, CD3⁺/CD19⁺, or TCRαβ⁺/CD19⁺ depletion), and (2) in vivo T-cell depletion using unmanipulated grafts followed by post-transplant cyclophosphamide (PTCy) for GvHD prophylaxis. Furthermore, the presence of donor-specific anti-HLA antibodies (DSA) has been associated with an increased risk of both graft failure and poor graft function. Several approaches for desensitization ameliorate this risk when a suitable donor without DSA is not available. In addition to advances in supportive care, the recent demonstration that stable mixed chimerism post-HCT sufficiently sustains symptom-free status has opened the door for less toxic treatment approaches yielding excellent survival outcomes. Though late effects remain uncertain, the goal of finding the least toxic conditioning regimen while providing the highest rate of donor engraftment draws closer within reach. In this review, the authors aim to present the latest findings, challenges, and treatment modalities of this life-saving modality.
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View all citing articles on Scopus

³: Dr. Hisanori Mayumi, Department of Cardiovascular Surgery, National Kyushu Medical Center Hospital, 1-8-1 Jigyohama, Chuo-ku, Fukuoka City, 810 Japan

View full text

Cyclophosphamide-Induced Immunological Tolerance: an Overview

Abstract

Drug-induced immunological tolerance

Nature

Alteration of homograft response by antimetabolites

Ann. N. Y. Acad. Sci.

Inhibition of the inductive phase of antibody formation by 6mercaptopurine examined by the transfer of isolated cells

Nature

6-Mercaptopurine in immunological responsiveness

Nature

The rejection of renal homografts inhibition in dogs by 6mercaptopurine

Lancet

Drug-induced immunological -tolerance- for homotransplantation

Transplant. Bull.

Induction of tolerance to skin homografts in adult mice treated with 6-mercaptopurine

Transplant. Bull.

Specific immune tolerance to anaphylactic sensitization (egg albumin) induced in the guinea pig by cyclophosphamide (Cytoxan)

J. Allergy

Prolongation of homograft survival in mice with single doses of cyclophosphamide

Nature

Drug effects on survival of homografts of skin

Arch. Surgery

Suppression of tissue immunity by cyclophosphamide

Transplantation

A comparison of the effects of selected cytotoxic agents on allogeneic skin graft survival in rat

Bull. Johns Hopkins Hosp.

Curative potencies against amanitin poisoning by cytochrome C

Science

Studies on cyclophosphamide-induced tolerance to sheep erythrocytes

J. Exp. Med.

Prolongation of skin graft survival in mice by pretreatment with H-2 antigen and cyclophosphamide.'Rev

Eur. Etudes. Clin. Biol.

Prolonged chimerism of the lymphoid tissue obtained in adult mice with the aid of cyclophosphamide

Bull. Exp. Biol. Med.

Cyclophosphamide-induced immunologic tolerance to skin homografts

Surg. Forum

Cyclophosphamide and human organ transplantation

Lancet

Brief communication: effects of chronic cyclophosphamide and methotrexate treatment on skin allograft survival in mice and rats

J. Natl. Cancer Inst.

Mechanisms of immunosuppression: effects of cyclophosphamide on cellular immunity

Blood

The induction and abolition of specific immunosuppression of heart allografts in rats by use of donor blood and cyclophosphamide

J. Immunol.

Specific unresponsiveness to skin allografts in mice

V. Synergy between donor tissue extract, procarbazine hydrochloride, and antilymphocyte serum in creating a long-lasting unresponsiveness mediated by suppressor T cells. Transplantation

Cyclophosphamide-induced chimera-type tolerance to allografts: an overview of drug-induced immunological tolerance Fukuoka

Acta Med.

Cell-free antigenic material employed to produce tolerance to skin grafts: tissue sources,

preservation, dose requirements and the effects of combined use with azathioprine and sublethal irradiation. Ann. N. Y. Acad. Sci.

Cell migration, chimerism, and graft acceptance

Lancet

Chimerism after liver transplantation for type IV glycogen storage disease and type 1 Gaucher's disease

N. Engl. J. Med.

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J. Immunol.

Hamster-to-rat heart and liver xenotransplantation with FK506 plus antiproliferative drugs

Transplantation

Drug-induced tolerance to allografts in mice

I. Difference between tumor and skin grafts. Transplantation

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VII. Optimal protocol and mechanism of cyclophosphamide-induced tolerance in an H-2 haplotype-identical strain combination. Transplant. Proc.

Druginduced tolerance of allografts in mice

XIII. Tolerance to the H-Y antigen. Transplant. Proc.

allograft tolerance in adult mice induced across fully allogeneic (multimajor H-2 plus multiminor histocompatibility) antigen barriers by a tolerance-inducing method using cyclophosphamide

J. Exp. Med.

Recent state of cyclophosphamide-induced skin allograft tolerance in mice

Immunobiology

A major difference in the mechanisms of neonatally induced tolerance and cyclophosphamide-induced tolerance

Transplantation.

Drug-induced tolerance to allografts in mice II

Tolerance to tumor allografts of large doses associated with rejection of skin allografts and tumor allografts of small doses. Immunobiology

Drug-induced tolerance to allografts in mice

IV. Mechanisms and kinetics of cyclophosphamide-induced tolerance. Transplantation

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X. Augmentation of split tolerance in murine combinations disparate at both H-2 and non-H-2 antigens by the use of spleen cells from donors preimmunized with recipient antigens. Immunobiology