Delayed Tolerance Through Mixed Chimerism

Inclusion criteria

• Male or female 18-65 years of age.
• Kidney transplant recipients from either LD or DD, with cryo-preserved HSCs available, good renal function (GFR\>60 ml/min/1.73m2), normal current allograft biopsy, and no history of documented rejection episodes.
• First or second renal transplant.
• Use of FDA-approved methods of contraception (those with less than a 3% failure rate) by all recipients from the time that study treatment begins until 104 weeks (24 months) after renal transplantation. (For further information on FDA- approved methods of contraception, see https://www.fda.gov/media/150299/download
• Ability to understand and provide informed consent.
• Negative COVID-19 test during screening and two days prior to HSC transplantation (HSCT). Deceased Donor (DD)
• Male or female 18-70 years of age.
• Consent to donate vertebral bones is obtained from the donor family.
• HSCs are successfully cryopreserved and saved \>2X106/kg (CD34+ cells) of the recipient.
• Acceptable laboratory parameters (hematology in normal or near-normal range. Liver function \<2 times the upper limit of normal, and normal creatinine)
• Negative for viral infection with HbsAg, HIV, HCV, or HTLV-1
• Negative COVID-19 test at the time of HSC procurement. Living Donor (LD)
• Willingness to provide HSCs by leukapheresis or bone marrow aspiration.
• Negative serologic pregnancy test for females of childbearing potential
• Good general health as per conventional evaluation for kidney donation.
• Acceptable laboratory parameters (hematology in normal or near normal range. Liver function \<2 times the upper limit of normal, and normal creatinine)
• Negative for viral infection with HbsAg, HIV, HCV, or HTLV-1.
• Cardiac/pulmonary function within normal limits (CXR, ECG).
• Ability to understand and provide informed consent.
• Meets standard institutional criteria for PBSC collection.
• Negative COVID-19 test during screening and two days prior to PBSC collection. Recipient

Exclusion criteria

• ABO blood group-incompatible renal allograft.
• Evidence of anti-HLA antibody (donor specific with an MFI \>1000) as assessed by routine methodology (Luminex)
• Previous history of biopsy proven rejection.
• Persistent Leukopenia (WBC less than 2,000/mm3) or thrombocytopenia (\<100,000/mm3).
• Seropositivity for HIV-1, hepatitis B surface or core antigen, or hepatitis C virus (confirmed by hepatitis C virus RNA).
• Active infection
• Left ventricular ejection fraction \< 40% as determined by TTE or clinical evidence of heart failure.
• Forced expiratory volume FEV1 or DLCO \< 50% of predicted.
• Lactation or pregnancy.
• History of cancer (following the American Transplant Society Guidelines)
• Underlying renal disease etiology with high risk of disease recurrence in the transplanted kidney (such as focal segmental glomerulosclerosis). Autoimmune diseases such as Lupus and Thrombotic Thrombocytopenic Purpura.
• Enrollment in other investigational drug studies within 30 days prior to enrollment.
• Abnormal (\>2 times lab normal) values for (a) liver function chemistries (ALT, AST, AP), (b) bilirubin, (c) coagulation studies (PT, PTT), or any patients on chronic anticoagulation therapy.
• Allergy or sensitivity to any component of Siplizumab, fludarabine, CP, tacrolimus, MMF or rituximab.
• Any medical condition that the investigator deems incompatible with participation in the trial. This includes a history of alcohol abuse or illicit drug use/dependence.
• Non-insulin dependent diabetes (NIDDM) without good blood glucose control (HbA1c\<7). Severe retinopathy, gastroparesis, or severe neuropathy which prevent subject's normal independent daily activities.