Benedict Cosimi

Epstein-Barr Virus Infection in Renal Transplant Recipients: Effects of Antithymocyte Globulin and Interferon

We studied Epstein-Barr (EB) virus excretion and antibody in 41 renal transplant recipients enrolled in a placebo-controlled trial of human leukocyte interferon. Half the patients were also treated with antithymocyte globulin. Epstein-Barr virus excretion occurred more often in recipients of cadaver kidneys (P = 0.03) and those receiving antithymocyte globulin (P = 0.04) and less often in patients given interferon (P = 0.08). Antibody to viral capsid antigen increased fourfold or more in 12 of 22 patients treated with antithymocyte globulin and in none of the non-antithymocyte globulin-treated group (P = 0.0002). Antibody to the restricted component of early antigen rose fourfold or more in eight patients and appeared related to the occurrence of syndromes similar to those attributed to cytomegalovirus in transplant recipients. We conclude that increasing immunosuppression augments the rate of EB virus reactivation and that EB virus may be an important pathogen in heretofore ill-defined syndromes.

OKT3: First-Dose Safety and Success

Orthoclone OKT3 is a murine monoclonal antibody that has been shown to be effective in reversing acute rejection episodes. In a randomized, multicenter trial, Orthoclone OKT3 reversed 94% of acute rejection episodes; conventional treatments reversed only 75%. However, early trials also disclosed some limitations of OKT3 therapy, such as a severe febrile or bronchospastic response following the initial injection, recurrent rejection episodes after discontinuation of OKT3 administration, or the hosts production of antibodies to the murine immunoglobulin. In later experiments modifications and precautions applied to the therapeutic helped to control first-dose reactions and decrease antibody production from 86 to 39%. Furthermore, recurrent rejection episodes occurring after discontinuation of OKT3 therapy in azathioprine-prednisone-treated patients have been shown to be reversible in most cases: a 75% rate of long-term (14- to 26-month) allograft survival has been achieved in these patients. More recently, OKT3 treatment administered to allograft recipients receiving cyclosporin has been shown to benefit 15-20% of patients when administered at the time of rejection. This combination approach not only reverses the rejection, but also seems to significantly reduce the incidence of subsequent rejection episodes. OKT3 has raised clinical immunosuppressive specificity to a higher level than previous therapies such as steroids or cytotoxic agents. OKT3 appears to be safe and effective therapy for patients receiving cyclosporin or azathioprine-prednisone therapy. Despite certain unresolved limitations, it may be a successful prototype for future, even more highly specific, immunosuppressive protocols.

Dynamics of B Cell Recovery In Kidney/Bone Marrow Transplant Recipients

Background Previous studies identified B cell gene signatures and predominance of specific B cell subsets as a marker of operational tolerance after kidney transplantation. These findings suggested a role for B cells in the establishment or maintenance of tolerance. Here we analyzed B cell recovery in 4 subjects, 3 of whom achieved tolerance after combined kidney/bone marrow transplantation. Methods Peripheral B cell subsets were examined longitudinally by flow cytometry. Immunoglobulin heavy chain repertoire analysis was performed using next-generation sequencing. Lastly, the patients’ serum reactivity to HLA was assessed by Luminex. Results B cell counts recovered approximately 1 year posttransplant except for 1 subject who experienced delayed reconstitution. This subject resumed immunosuppression for acute rejection at 10 months posttransplant and underwent preemptive retransplantation at 3 years for chronic rejection. B cell recovery was accompanied by a high frequency of CD20 + CD24highCD38high transitional B cells and a diversified clonal repertoire. However, all 4 subjects showed prevalence of CD20 + CD27+ memory B cells around 6 months posttransplant when B cell counts were still low and the clonal B cell repertoire very limited. The predominance of memory B cells was also associated with high levels of somatically mutated immunoglobulin heavy chain variable sequences and transient serum reactivity to HLA. Conclusions Our observations reveal the presence of memory B cells early posttransplant that likely escaped the preparative regimen at a time consistent with the establishment of tolerance. Further studies are warranted to characterize the functional properties of these persisting memory cells and evaluate their potential contribution to tolerance induction.