Homeostatic proliferation is a normal physiological process triggered by lymphopenia to maintain a constant level of T cells. It becomes the predominant source of new T cells in adulthood after thymus regression. T cells that have undergone homeostatic proliferation acquire the memory phenotype, cause autoimmune disease, and are resistant to tolerance induction protocols. Transplantation is a rare example in which lymphopenia is deliberately induced for its immunosuppressive effect. However, it is not known whether the homeostatic proliferation that follows will have the opposite effect and accelerate rejection. We show that T cells that have undergone homeostatic proliferation acquire a memory phenotype, spontaneously skews toward the Th1 phenotype, even in the absence of antigenic stimulus. Interestingly, in contrast, the percentage of Foxp3+ regulatory T cells increased by 28-fold following homeostatic proliferation. Using a mouse life-sustaining kidney transplant model, we showed that T cells that have gone through homeostatic proliferation in lymphopenic hosts transformed chronic rejection to acute rejection of a single MHC class II-mismatched kidney allograft. T cells that have undergone homeostatic proliferation consistently cause reliable rejection even when bona fide memory T cells cannot. These functional changes are long-lasting and not restricted to the acute phase of homeostatic proliferation. Our findings have important implications for tolerance induction or graft-prolonging protocols involving leukocyte depletion such as irradiation bone marrow chimera, T cell-depleting Abs, and lymphopenia induced by infections such as CMV and HIV.

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Kidney transplantation is the best form of treatment for end-stage renal failure. Despite a high success rate with graft survival of more than 90% in the 1st year, acute rejection remains the principal cause of graft loss within the 1st year of transplantation and contributes to chronic damage. Although serum creatinine is a good measurement of renal function, rejection can only be reliably diagnosed by histological analysis of biopsy samples.

dialysis center in the month preceding viral infection and during infection and found a critical difference (Figure 1). In the patients who tested positive for COVID-19, the mean (AESD) ferritin levels in March (before viral infection) and at diagnosis were 584 AE 318 and 1446 AE 1261 ng/ml, respectively, which was a mean increase of 275%. Interestingly, ferritin levels were increased at diagnosis in the 5 asymptomatic patients as well as in the patients with symptoms (mean AE SD, 1209 AE 1292 and 1535 AE 1280 ng/ml, respectively). Ferritin levels remained stable or decreased very slowly during the whole period of sickness in almost all patients. The pathophysiological mechanisms underlying high ferritin levels have not been totally explained at this time, and some investigators have reported a cytokine storm syndrome or macrophage activation syndrome; however, in our cohort, ferritin levels were not correlated with C-reactive protein (data not shown). 4,5 Screening for COVID-19 in hemodialysis centers is crucial so that infected patients can be isolated and to protect noninfected patients. Ferritin could be a helpful, available, and easy-to-use screening tool for the disease, although we believe that more research still is needed.