scholarly journals Donor-specific tolerance induction in organ transplantation via mixed splenocytes chimerism

2013 ◽  
Vol 173 (2) ◽  
pp. 173-178 ◽  
Author(s):  
S. Yamazaki ◽  
A. Kanamoto ◽  
T. Takayama
Keyword(s):  
Organ Transplantation ◽  
Tolerance Induction ◽  
Donor Specific Tolerance ◽  
Specific Tolerance

Donor Specific Tolerance Of Renal Allografts Following Haploidentical In Utero Hematopoietic Cell Transplantation In The Canine Model

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2007-2007
Author(s):  
Erik G. Pearson ◽  
Jesse D Vrecenak ◽  
Tricia R Bhatti ◽  
William H. Peranteau ◽  
Alan W. Flake
Keyword(s):  
Renal Transplantation ◽  
Organ Transplantation ◽  
Cell Transplantation ◽  
Murine Model ◽  
Hematopoietic Cell Transplantation ◽  
Canine Model ◽  
Positive Control ◽  
Donor Chimerism ◽  
Donor Specific Tolerance ◽  
Specific Tolerance

Abstract Introduction In utero hematopoietic cell transplantation (IUHCT) can result in allogeneic mixed hematopoietic chimerism and associated donor specific tolerance (DST). We have reported a 1-2% donor chimerism threshold for consistent DST in the murine model as defined by the ability to enhance engraftment postnatally with a same donor minimal conditioning BMT, and have confirmed this finding in the canine model of IUHCT. Recently, we have optimized the canine model and achieved higher levels of chimerism (average>10%). As prenatal tolerance induction for postnatal organ transplantation is one of the clinical goals of IUHCT, we hypothesized that the presence of donor chimerism (>2.0%) after haploidentical IUHCT in the canine model would be sufficient to allow same donor renal transplants without immunosuppression. Method Stable mixed hematopoietic macrochimerism was documented by VNTR after haploidentical IUHCT performed at 40 days gestation using maternal donor BM cells in 4 pups (chimerism levels 3-38%). One positive control canine with no detectable chimerism following IUHCT also underwent haploidentical renal transplantation. Renal transplantation was performed from the maternal donor at ages between 12 and 18 months, and the pups were serially followed by ultrasound of the graft, blood chemistry and urinalysis post transplant. At 60 days an open biopsy of the allograft was taken and at 6 months a graft nephrectomy was performed for histologic analysis. Results Following transplantation, all recipients demonstrated blood flow to the renal cortex and all laboratory values were within normal ranges. At 60 days and 6 months 3 of the 4 recipients demonstrated a graft without evidence of acute or chronic rejection. The recipient with the lowest level of chimerism (3%) demonstrated evidence of mild interstitial nephritis (Banff class 1 rejection) following transplantation at the time of renal biopsy which increased in severity to severe interstitial fibrosis and moderate tubular atrophy (Banff class 3 rejection) at the time of graft nephrectomy. The positive control canine without detectable chimerism demonstrated clinical and histologic evidence of acute rejection within one week of transplantation. Conclusion Our results support the ability of IUHCT to induce DST for haploidentical organ transplantation, in a large animal model, without the need for immunosuppression. In agreement with previous studies in the murine model there appears to be a threshold level of donor chimerism required for associated DST. Although our numbers are not adequate to establish absolute thresholds of chimerism predictive of DST for organ transplantation, it appears to be slightly higher than the 1-2% threshold established for cellular transplantation. Disclosures: No relevant conflicts of interest to declare.

Durable Chimerism, Absence of Graft-Versus-Host Disease and the Induction of Donor Specific Tolerance in Recipients of HLA Disparate Living Donor Kidney Transplants and Therapeutic Cell Transfer

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 832-832
Author(s):  
Joseph Leventhal ◽  
Michael Abecassis ◽  
Joshua Miller ◽  
Lorenzo Gallon ◽  
Kadiyala Ravindra ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Living Donor ◽  
Chronic Gvhd ◽  
Tolerance Induction ◽  
Transplant Recipients ◽  
Graft Versus Host ◽  
Post Transplant ◽  
Equity Ownership ◽  
Donor Specific Tolerance ◽  
Specific Tolerance

Abstract Abstract 832 Background: Renal transplantation is the preferred therapeutic approach for end-stage renal disease. However, the chronic use of non-specific immunosuppressive agents (IS) is costly and has significant toxicities including opportunistic infection, an increased rate of malignancy, nephrotoxicity, and other end-organ damage. The induction of donor-specific tolerance would address these limitations. Bone marrow chimerism is associated with tolerance to transplanted organs and tissues. However, the toxicity associated with conventional hematopoietic stem cell transplants (HSCT), primarily graft-versus-host disease (GVHD), and the need for aggressive ablative conditioning, has limited the therapeutic application of HSCT to tolerance induction. We have identified a novel tolerogenic bone marrow cell population of CD8+/TCR− facilitating cells (FC) that enhances engraftment of bone marrow in mismatched recipients without causing GVHD. The discovery of FC is an important finding as it opens the door to employing HSCT as a viable cell-based approach for tolerance induction. Methods: We report here the long-term follow-up for 8 HLA mismatched living donor renal transplant recipients enrolled in a tolerogenic protocol involving low-intensity conditioning (fludarabine, cyclophosphamide [50 mg/kg, day −3, +3], 200 cGy TBI) followed by HSCT and renal transplantation. Lymphocyte depleting antibody therapy was not employed. Patients received a living donor kidney transplant on day 0, followed by infusion of cryopreserved FC-enriched donor-derived CD34+ HSC (FCRx) on day +1 (0.49–4.48 × 106 FC/kg recipient body weight) and a calculated dose of T cells (Table). All subjects were discharged by post-operative day 3 and managed as outpatients. Maintenance IS consisted of tacrolimus and MMF without steroids. Weaning of immunosuppression was designed to occur over a one-year period. At 6 months, if chimerism was present and renal function and biopsy normal, the MMF was discontinued; at 9 months the tacrolimus was decreased to trough levels of 3 to 5; and at 12 months, tacrolimus was discontinued. Characteristics and degree of HLA mismatch are shown in the table. Results: The patients are now 13 to 30 months post-transplant. All patients demonstrated peripheral blood macrochimerism post-transplant, ranging from 6% to 100% at 1 month by STR molecular analysis. No patient developed acute GVHD, showed evidence of engraftment syndrome, or has developed evidence of chronic GVHD. Chimerism was lost in two of the patients at 3 and 6 months post-transplant (NW 1 and 4). These subjects received an FCRx containing the fewest numbers of FC. Renal allograft loss occurred in one patient who developed sepsis and myelosuppression following an atypical viral infection 2 months post-transplant. He was successfully rescued with banked autologous HSCT. He was subsequently re-transplanted. The seven remaining patients demonstrate donor-specific hyporesponsiveness. Five have been successfully withdrawn entirely from IS, with one patient now off all IS for 15 months (30 months post-transplant). Four of these five subjects had mismatched unrelated (UR) donors (Table). None developed anti-donor antibody by flow crossmatch. Adverse events have included single dermatome herpes zoster reactivation in 2 patients which resolved. No clinically significant CMV or polyoma viral infections have occurred. Conclusions: Low intensity conditioning in conjunction with FC-enriched HSCT can safely achieve high level, durable donor chimerism in unrelated and related HLA-mismatched kidney transplant recipients without acute or chronic GVHD. This is associated with stable renal function and successful IS withdrawal. Disclosures: Tollerud: Regenerex, LLC: Equity Ownership. King:Regenerex, LLC: Employment. Ildstad:Regenerex, LLC: Equity Ownership.

scholarly journals The Need for Inducing Tolerance in Vascularized Composite Allotransplantation

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Kadiyala V. Ravindra ◽  
Hong Xu ◽  
Larry D. Bozulic ◽  
David D. Song ◽  
Suzanne T. Ildstad
Keyword(s):  
Solid Organ Transplantation ◽  
Tolerance Induction ◽  
Mixed Chimerism ◽  
Future Research ◽  
Solid Organ ◽  
Vascularized Composite Allotransplantation ◽  
Split Tolerance ◽  
Donor Specific Tolerance ◽  
Specific Tolerance

Successful hand and face transplantation in the last decade has firmly established the field of vascularized composite allotransplantation (VCA). The experience in VCA has thus far been very similar to solid organ transplantation in terms of the morbidity associated with long-term immunosuppression. The unique immunological features of VCA such as split tolerance and resistance to chronic rejection are being investigated. Simultaneously there has been laboratory work studying tolerogenic protocols in animal VCA models. In order to optimize VCA outcomes, translational studies are needed to develop less toxic immunosuppression and possibly achieve donor-specific tolerance. This article reviews the immunology, animal models, mixed chimerism & tolerance induction in VCA and the direction of future research to enable better understanding and wider application of VCA.

Specific Tolerance Induction and Organ Transplantation

1998 ◽  
Vol 31 (1-2) ◽  
pp. 131-142 ◽  
Author(s):  
Anneke De Vries-Van Der Zwan ◽  
Arit C. Besseling ◽  
Marjolein A. Van Der Pol ◽  
Leo P. De Waal ◽  
Claire J. P. Boog
Keyword(s):  
Organ Transplantation ◽  
Tolerance Induction ◽  
Specific Tolerance

Donor-specific tolerance induction in composite tissue allografts

1998 ◽  
Vol 176 (5) ◽  
pp. 418-421 ◽  
Author(s):  
Robert D Foster ◽  
Larry Fan ◽  
Michael Niepp ◽  
Christina Kaufman ◽  
Timothy McCalmont ◽  
...  
Keyword(s):  
Tolerance Induction ◽  
Composite Tissue ◽  
Donor Specific Tolerance ◽  
Specific Tolerance

scholarly journals Improving the Safety of Tolerance Induction: Chimerism and Cellular Co-Treatment Strategies Applied to Vascularized Composite Allografts

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Wei-Chao Huang ◽  
Jeng-Yee Lin ◽  
Christopher Glenn Wallace ◽  
Fu-Chan Wei ◽  
Shuen-Kuei Liao
Keyword(s):  
Treatment Strategies ◽  
Tolerance Induction ◽  
Long Bone ◽  
Myeloablative Conditioning ◽  
Graft Versus Host ◽  
Hematopoietic Chimerism ◽  
Donor Specific Tolerance ◽  
Specific Tolerance ◽  
Vascularized Bone

Although vascularized composite allografts (VCAs) have been performed clinically for a variety of indications, potential complications from long-term immunosuppression and graft-versus-host disease remain important barriers to widespread applications. Recently it has been demonstrated that VCAs incorporating a vascularized long bone in a rat model provide concurrent vascularized bone marrow transplantation that, itself, functions to establish hematopoietic chimerism and donor-specific tolerance following non-myeloablative conditioning of recipients. Advances such as this, which aim to improve the safety profile of tolerance induction, will help usher in an era of wider clinical VCA application for nonlife-saving reconstructions.

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