番茄社区

For three children, their newly transplanted kidneys might never require them to take immunosuppressive drugs.

Along with the kidney they got from a parent due to the rare T-cell immunodeficiency and primary kidney failure syndrome they had (Schimke immuno-osseous dysplasia), the children got reduced-intensity conditioning and αβ T-cell–depleted and CD19 B-cell–depleted hematopoietic bone marrow from that haploidentical parent.

"Full donor hematopoietic chimerism and functional ex vivo T-cell tolerance was achieved, and the patients continued to have normal renal function without immunosuppression at 22 to 34 months after kidney transplantation," reported Alice Bertaina, MD, PhD, of Stanford University in California, and colleagues in the .

It's a notable step forward, stated Thomas Spitzer, MD, of Massachusetts General Hospital in Boston, and David Sachs, MD, of Columbia University in New York City, in an .

"The separation of [graft-versus-host disease or GVHD] from the graft-versus-tumor effect and the induction of functional immune tolerance, defined by the absence of a destructive immune response in the absence of systemic immunosuppression, have been considered the 'Holy Grail' of HSCT [hematopoietic stem-cell transplantation] and solid-organ transplantation, respectively," they wrote.

"Freedom from immunosuppression after organ transplantation has a tremendous potential upside, since lifelong immunosuppressive therapy is sometimes complicated by debilitating or life-threatening complications, including but not limited to serious infections and secondary cancers," Spitzer and Sachs added.

Some prior success in that regard has accrued in adult transplant clinical trials. and long-term antitumor responses were seen in seven of 10 cases of HLA-matched and haploidentical combined bone marrow and kidney transplants performed in patients with multiple myeloma and end-stage renal disease. Outside of the cancer setting, other small have combined HSCT and kidney transplantation with immune tolerance in the of patients.

The case series from Bertaina's group was a "remarkable experience" that shows the "potential of combined or sequential HSCT and kidney transplantation to correct disorders of hematopoiesis and immunodeficiency and to induce tolerance of the kidney allograft," according to the editorialists.

The way the stem cells were processed, with αβ T-cell depletion, removes the type of immune cells that cause GVHD and enables genetically half-matched transplants.

The immunodeficiency of Schimke immuno-osseous dysplasia "undoubtedly contributed to the achievement of successful donor HSCT engraftment without GVHD across an HLA barrier, despite T-cell depletion of the donor inoculum," Spitzer and Sachs noted. "Therefore, the specifics of this strategy may not be applicable to all tolerance induction approaches. Nevertheless ... it is a strategy that could also be considered for patients with other conditions in which sustained full donor chimerism is desirable."

The researchers noted that another group had previously tried something similar in Schimke immuno-osseous dysplasia but from HSCT-related causes, potentially due to increased sensitivity to DNA-damaging agents used in myeloablative conditioning regimens.

In their series of the first three patients treated with what they called "dual immune/solid organ transplant," the patients got antithymocyte globulin (7.5 mg/kg), then fludarabine (1 mg/kg/day for 4 days) and cyclophosphamide (1,200 mg/m²), followed by total-body irradiation (200 cGy) and rituximab (200 mg/m²) to prepare for the HSCT.

Once donor myeloid and lymphoid chimerism after HSCT had been confirmed (at 5, 5.5, and 10 months for the individual patients), the living-donor kidney was transplanted from the haploidentical parent who had donated the HSCT. The patients received intraoperative methylprednisolone and postoperative low-dose oral prednisone and tacrolimus to reduce reperfusion inflammation, which were tapered off by day 30 and no further immunosuppression given.

No clinical signs of rejection were seen in the patients. Renal function is normal at 22 to 34 months post-transplantation. Two patients have had a protective response to subsequent vaccinations, and the third was awaiting titer data at the time of publication.

Peripheral blood mononuclear cells at 1 year after kidney transplantation showed functional tolerance to stimulator cells derived from their donor parent -- "and, therefore, potentially unable to mediate graft rejection even in the absence of immune suppression," the researchers noted. But their immune cells reacted as normal and proliferated in the presence of stimulator cells derived from their non-donor parent or a healthy, unrelated control.

"Further studies will be needed to determine whether these outcomes can be achieved in allograft recipients with intact pretransplantation T-cell immunity and hematopoiesis," Bertaina's group said.

They are now expanding the protocol to children who have had an initial kidney transplant that was rejected and plan to look at how to extend it to other solid organ transplants, including from deceased donors.

"That's a challenge, but it's not impossible," Bertaina said in a statement. "We'll need 3 to 5 years of research to get that working well."

Comment