The impact of non-classical symptoms of acute GvHD

Classically, the main organs that have been discussed with reference to acute graft-versus-host disease (aGvHD) have been the intestines, skin, and liver. However, other non-classical organs are starting to receive more attention. In fact, many of the symptoms that are being recorded were previously masked or mistaken for signs of conditioning toxicity and are now being recognized to be the result of aGvHD in non-classical organs. These non-classical targets for aGvHD include the central nervous system (CNS), lungs, thymus, kidneys, bone marrow, and the ovaries and testis.

Robert Zeiser and Takanori Teshima recently published an article entitled ‘Non-classical manifestations of acute GvHD’ in Blood,¹ and the GvHD Hub was fortunate enough to be able to speak with both authors about their latest work (see interviews below).

CNS and lung

Although the CNS is traditionally thought of as a sterile environment, results from histologic samples have demonstrated that effector memory T cells infiltrate the brain in mouse transplant models resulting in apoptotic death of neurons. However, it has been shown that GvHD prophylaxis can inhibit the infiltration of T cells into the CNS. Mice who have been transplanted without immunosuppression have symptoms of impaired cognition, and studies have demonstrated neurologic deficits and abnormal magnetic resonance imaging (MRI) findings in patients developing GvHD. The identification of CNS GvHD may improve patient outcomes.

Lung aGvHD has been recorded to occur in 3–15% of patients who have an allogeneic transplant although symptoms can be hard to distinguish from toxicity following conditioning. The signs of acute lung GvHD seen on histologic analyses include peribronchial and interstitial lymphocytic infiltrates and acute degeneration of the bronchial epithelium.

Robert Zeiser discusses this, and more, in his video below.

Thymus and bone marrow

The thymus is very sensitive to the atrophy resulting from the action of alloreactive T cells in mouse models of aGvHD. In turn, this causes depletion of the T-cell receptor (TCR) repertoire and T-cell deficiency. A decrease in the expression of tissue-restricted antigens by the thymus exacerbates GvHD by increasing the production of autoreactive CD4+ T cells.

The bone marrow was also found to be a target of non-classical GvHD manifestations with osteoblasts and mesenchymal stromal cells being damaged. This leads to impaired immune reconstitution in patients, which Takanori Teshima comments on in the video below.

Kidney, ovaries, and testes

aGvHD has been recorded both in mouse models and humans, and in the latter, 70% of patients undergoing allogeneic transplant show signs of acute kidney injury. It is difficult to quantify how much of the damage to the kidney is a result of GvHD as many medications may cause kidney injury such as calcineurin inhibitors. It is, therefore, more likely that late phase kidney injury may be indicative of aGvHD, as medicines will have been tapered in most patients.

Mating experiments in mice looking at the effect of aGvHD on the ovaries showed that fewer newborn mice were born to mothers that had received an allogeneic transplant compared with a syngeneic transplant. This effect was only noted in mice that were not given GvHD prophylaxis. In mice that received immunosuppressive treatment, fertility was restored and ovarian GvHD was prevented. However, it should be noted that studies have found donor T cells close to granulosa cells in the ovarian follicles, and this was connected to impaired maturation of the ovarian follicles and hormone production.

The testes are also affected by aGvHD and infertility issues can be a problem for human patients following allogeneic transplant. However, this is more likely to be the result of irradiation and damage from chemotherapy. It is thought that the contribution of GvHD to this effect is small, although there are reports of granulosa and Leydig cellular impairment occurring during aGvHD that correlates with gonadal insufficiency and azoospermia.

Conclusion

While the authors noted that GvHD prophylaxis was not given in many of the in vivo studies, the evidence that they provide is still valuable in demonstrating how patients can be affected. If these symptoms can be detected early, there is more opportunity for improving the quality of life and survival for patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). In addition, understanding the impact of aGvHD on non-classical organs may aid the development of novel strategies for this disease.